- Jesse Spencer as Lieutenant Matthew Casey
- Taylor Kinney as Lieutenant Kelly Severide
- Monica Raymund as Firefighter/Paramedic Gabriela Dawson
- Kara Killmer as Paramedic Sylvie Brett
- David Eigenberg as Firefighter Christopher Herrmann
- Yuri Sardarov as Firefighter Brian "Otis" Zvonecek
- Joe Minoso as Firefighter Joe Cruz
- Christian Stolte as Firefighter Randy "Mouch" McHolland
- Steven R. McQueen as Firefighter Jimmy Borrelli (Eps. 1–2)
- Miranda Rae Mayo as Firefighter Stella Kidd
- Eamonn Walker as Battalion Chief Wallace Boden
- Jon Seda as Investigator Antonio Dawson
- Carl Weathers as State's Attorney Mark Jefferies
- Jason Beghe as Sergeant Hank Voight
- Sophia Bush as Detective Erin Lindsay
- Jesse Lee Soffer as Detective Jay Halstead
- Marina Squerciati as Officer Kim Burgess
- Amy Morton as Desk Sergeant Trudy Platt
- Elias Koteas as Detective Alvin Olinsky
- Barbara Eve Harris as Deputy Chief Emma Crowley
- Li Jun Li as Officer Julie Tay
- America Olivo as Laura Dawson
- Zach Garcia as Diego Dawson
- Alina Taber as Lexi Olinsky
- Nick Gehlfuss as Dr. Will Halstead
- Torrey DeVitto as Dr. Natalie Manning
- Yaya DaCosta as Nurse April Sexton
- Brian Tee as Dr. Ethan Choi
- Oliver Platt as Dr. Daniel Charles
- Rachel DiPillo as Dr. Sarah Reese
- Marlyne Barrett as Maggie Lockwood
- S. Epatha Merkerson as Sharon Goodwin
- Randy Flagler as Firefighter Harold Capp
- Anthony Ferraris as Firefighter Tony, Rescue Squad 3
- DuShon Brown as Connie
- Robyn Coffin as Cindy Herrmann
- Kamal Angelo Bolden as Firefighter Jason Kannell, Squad 6/Squad 3
- Treat Williams as Benny Severide
- Jeff Hephner as Jeff Clarke
- Melissa Ponzio as Donna Robbins-Boden
- Gordon Clapp as Chaplain Orlovsky
- Daniel Zacapa as Ramón Dawson
- Charlotte Sullivan as Anna Turner
- Nick Boraine as Dennis Mack
- Scott Elrod as Travis Brenner
- Lauren Stamile as Susan Weller
- Holly Robinson Peete as Tamara Jones
- Alex Weisman as Paramedic Chout
- Mia Hulen as Marcy Prescott
- Deanna Reed-Foster as Tina Cantrell
- Guy Burnet as Grant Smith
- Michael Hanrahan as Deputy District Chief Jim Anderson
|[[The Hose or the Animal]]||Writer: Michael Brandt and Derek Haas||Director: Joe Chappelle||October 11, 2016||#5x01|
|Dawson and Casey are back together after she has Louie. After spending the night with Severide, Stella finds out that her unstable ex-boyfriend Grant has escaped from psychiatric hold and is after her and Severide. Borelli files a grievance against Boden questioning his leadership following his brother's death. Dawson makes a difficult decision. Brett receives some unexpected attention from Antonio Dawson following a call.
|[[A Real Wake-Up Call]]||Writer: Andrea Newman & Michael Gilvary||Director: Reza Tabrizi||October 18, 2016||#5x02|
|Grant is charged with attempted murder and placed in psychiatric hold leading Stella to not press charges which infuriates Severide. Stella makes a difficult decision. Truck refuses to work with Jimmy because his grief was affecting his attitude. Mouch and Brett continue to pursue writing an erotic book. Also, Casey finds himself in a tough spot.
|[[A Scorched Earth]]||Writer: Sarah Kucserka & Veronica West||Director: Joe Chappelle||October 25, 2016||#5x03|
|Casey continues to pursue information into who tipped off the aldermen about Louie after the DCFS come after him and finds his consultant Susan Weller isn't who she said she was. Severide continues to hang out with local celebrity Travis Brenner (guest star Scott Elrod).
|[[Nobody Else Is Dying Today]]||Writer: Jill Weinberger||Director: Sanford Bookstaver||November 1, 2016||#6x04|
|Casey investigates a warehouse as alderman and does everything in his power to prevent a major disaster. Dawson and Brett deal with an advocate over an old lady's health. Otis and Cruz prank each other.
|[[I Held Her Hand]]||Writer: Roger Grant||Director: Reza Tabrizi||November 15, 2016||#5x05|
|Tensions rise when Severide and Casey disagree on a call when it's thought to be accidental or arson murder. Mouch and Brett run into trouble. Herrmann investigates into who is vandalizing 51 with graffiti.
|[[That Day]]||Writer: Michael A. O'Shea||Director: Dan Lerner||November 22, 2016||#5x06|
|Dawson runs into trouble with the CFD. Casey and Severide continue to investigate the Fire from the last call. Herrmann considers a promotion. Someone from Boden's past comes to see him. Brett takes her relationship with Antonio to the next level.
|[[Lift Each Other]]||Writer: Liz Alper & Ally Seibert||Director: Alex Chapple||November 29, 2016||#5x07|
|Casey is upset following a recent call. Cruz comes to Severide about Boden's stepson James and suspects abuse. Things take a dramatic turn at Antonio and Gabriela's parents wedding anniversary.
|[[One Hundred]]||Writer: Michael Brandt & Derek Haas||Director: Joe Chappelle||December 6, 2016||#5x08|
|Severide seeks treatment for a neck injury and runs into medical student Jeff Clarke, who asks him for a huge favour. Dawson and Casey run into a problems trying to adopt Louie permanently and make a life-changing decision.
|[[Some Make It, Some Don't]]||Writer: Drucilla Carlson||Director: Andrea Newman||January 3, 2017||#5x09|
|Louis' biological father confronts Casey and Dawson. Severide finds out he is a match for a patient for a bone marrow transplant but an accident sends Severide into a downward spiral. 51 responds to a hit and run accident involving Severide's car with Severide missing from the car.
Crossover between Chicago PD and Chicago Fire.
|[[The People We Meet]]||Writer: Sarah Kucserka & Veronica West||Director: David Rodriguez||January 17, 2017||#5x10|
|Severide gets into an accident during a call but forces the hospital to let him donate his bone marrow to Anna. Louie's father fights for full custody of him.
|[[Who Lives and Who Dies]]||Writer: Michael Gilvary||Director: Haze J. F. Bergeron III||January 24, 2017||#5x11|
|Dawson is upset after a call involving a young girl and an unknown pregnancy. Casey takes his anger out on 51. Casey makes a last minute decision following a call.
|[[An Agent of the Machine]]||Writer: Jill Weinberger||Director: Jann Turner||February 7, 2017||#5x12|
|51 is on high alert when an escaped criminal returns to kill Casey and target 51 - the CPD steps in. Brett and Antonio face difficulties after she is confronted by his ex-wife, Laura. A friend of Severide's dad comes to 51 to shadow him.
|[[Trading in Scuttlebutt]]||Writer: Roger Grant||Director: Reza Tabrizi||February 14, 2017||#5x13|
|Boden makes a decision overriding another newly promoted Chief Anderson. Fearing reputation damage, Anderson comes after 51. Severide has to decide whether to leave Chicago and become a Battalion Chief in Springfield.
|[[Purgatory]]||Writer: Michael Brandt & Derek Haas||Director: Joe Chappelle||February 21, 2017||#5x14|
|The team deals with being split up after being reassigned to different firehouses by Chief Anderson. Boden tries to repeal this and Severide tries to help while also trying to decide whether her should move to Springfield.
|[[Deathtrap]]||Writer: Andrea Newman||Director: Joe Chappelle||March 1, 2017||#5x15|
|The firehouse responds to a catastrophic fire at a party held inside a factory - and Olinsky's daughter is one of the dozens trapped inside; Severide eyes an open position at Med, hoping Anna can fill the role.
|[[Telling Her Goodbye]]||Writer: Michael A. O'Shea||Director: Reza Tabrizi||March 21, 2017||#5x16|
|The team is dragged into a hostage crisis after a gang takes shelter at 51; each member of the team works to keep the situation from escalating, especially Boden, who must lead at gunpoint.
|[[Babies and Fools]]||Writer: Michael Gilvary, Liz Alper, & Ally Seibert||Director: Holly Dale||March 28, 2017||#5x17|
|After a mysterious car crash, Dawson hunts down the culprit - whom she believes is a sociopath; Casey faces a new challenge from a disgruntled constituent; Severide worries Anna's homesickness will pull her away from Chicago for good.
|[[Take a Knee]]||Writer: Michael Brandt & Derek Haas||Director: Joe Chappelle||April 4, 2017||#5x18|
|Anna has a sudden and unexpected mood change after Kelly's father, Benny, also unexpectedly shows up after a fight. Herrmann focuses on some personal issues after his son Lee Henry gets into trouble at school.
|[[Carry Their Legacy]]||Writer: Michael O'Shea||Director: Reza Tabrizi||April 25, 2017||#5x19|
|When the squad's rig breaks down in the field, Casey reunites with his old friend and colleague Jason Kannell from Squad 6, whose crew gets assigned a temporary change of quarters until the rig issue is resolved. Dawson and Brett serve their time in retraining, both tackling the class in unique ways. Severide tries to remedy what is going on with Anna and finds support from unlikely sources. As Connie returns from her family engagement, the crew lays bets on how long her temporary replacement Marcy will last.
|[[Carry Me]]||Writer: Jill Weinberger||Director: Eric Laneuville||May 2, 2017||#5x20|
|Casey goes to drastic measures to help his friend Kannell. Lt. Severide helps an old widow come to terms with letting go, but realizes he may be the one needing help. Otis and Cruz deal with surprises when they find a new roommate to move in. Dawson and Brett get crafty to save a young girl.
|[[Sixty Days]]||Writer: Michael Gilvary||Director: Sanford Bookstaver||May 9, 2017||#5x21|
|Cruz finds himself in a bad spot when an off-duty incident begins to unravel, prompting Mouch to step in and offer help in hopes of avoiding serious consequences from the CFD. Casey goes head to head with a big politician to get his measure for first responders passed. Lt. Severide makes life difficult for newest team member Jason Kannell and Dawson gets an unexpected visit from her father.
|[[My Miracle]]||Writer: Michael Brandt & Derek Haas||Director: Michael Brandt||May 16, 2017||#5x22|
|A dangerous warehouse fire puts truck and squad at risk. Tensions are high for Dawson and Casey when Dawson's father overstays his welcome at their home. Meanwhile, Casey continues to fight for his first responders bill, Mouch makes a serious decision regarding his future and Herrmann goes to tremendous lengths to make a young boy smile. At the end of the episode, the firefighters find themselves trapped in a warehouse fire, Casey takes off the mask and says goodbye to Dawson knowing he will not get out alive.