Diego goes through a lot this season, developing an obsession with the assassination of President John F. Kennedy and his belief that Sir Reginald had something to do with it. His graceless attempts to find out the truth land him in an insane asylum where he meets Lila. She follows Diego as he escapes, helping him when the Swedish trio attack, and invites herself along for his mission. Diego quickly finds himself falling for Lila, though Number Five's suspicion of her keeps him from completely falling under her spell. However, when Lila saves Five instead of Diego during a heated altercation with the Swedes, Diego pushes her away, unable to shake the idea that she's up to something. (He's not wrong.)
Diego continues to hunt down Sir Reginald, determined to connect his adoptive father to the imminent murder of the president and stop him. The two engage in fisticuffs when Diego and Five break into Reginald's lab with the older man sneakily defeating Diego, but it only serves to fuel the latter's mission. When Reginald eventually sits down with all his children, he berates them for seeking him out to solve their problems. He then rips into Diego specifically, mocking his hero complex and incessant need to prove himself to his father. The encounter shatters Diego's self-esteem but he plows on, more determined than ever to uncover his father's grand scheme.
As Diego and his siblings rush to figure out how to stop the apocalypse, a formerly banished Lila kidnaps Diego to work under her as security for the Commission. While trapped, Diego manages to figure out what will cause the nuclear war that brings on the apocalypse and escapes to warn his siblings. He teams up with Allison and Klaus to save Vanya from being tortured by the government and winds up getting knocked out when Vanya's power overwhelms her, sending a head-piercing sound wave throughout the entire building she's being held in. Once Vanya is properly subdued, the siblings race to keep their father from assassinating President Kennedy, but they're unable to stop the fixed event and learn their father isn't present at the assassination.
In the end, Diego fights alongside his siblings against the Handler and Lila. He manages to convince Lila not to kill them, revealing that she's one of them, though she disappears before he can get her to stay with the Hargreeves. He is with his siblings as they travel forward to 2019 and wind up back at their home.