Major twists and character arcs across the series include:
- Season 2: Dr. Spencer Reid is kidnapped and tortured by Tobias Hankle, leading to a long battle with Dilaudid addiction. Elle Greenaway shoots an UnSub in cold blood and resigns from the FBI.
- Season 5: Serial killer George Foyet ("The Reaper") tracks down Hotch’s family. In a devastating phone call, Hotch listens as Foyet murders his ex-wife Haley before Hotch beats Foyet to death with his bare hands.
- Season 6: Emily Prentiss's past as an undercover Interpol agent catches up with her. Terrorist Ian Doyle pursues her, forcing the team to fake her death to protect her life, keeping the secret even from Reid and Garcia.
- Season 8: Reid falls in love with a scientist named Maeve whom he has never met in person; she is tragically executed right in front of him by her stalker Diane Turner.
- Season 12: "Mr. Scratch" (Peter Lewis) psychologically tortures Hotch and his son, forcing Hotch to enter Witness Protection and permanently step down from the BAU. Later, Reid is framed for murder in Mexico and sent to a brutal prison before being cleared.
- Season 15 Finale: The team defeats master serial killer Everett Lynch ("The Chameleon"), culminating in the destruction of the original BAU jet. Garcia leaves the unit for a non-profit role.
- Evolution (Seasons 16–19): The team battles Elias Voit ("Sicarius"), a mastermind who created an online network of serial killers during COVID-19 lockdowns. Voit is eventually captured and forced to act as an uneasy FBI consultant to catch copycats ("The Fan"), fundamentally altering the BAU's operational dynamics.