At the end, there's an epitaph for Bill Paxton, who died a little more than a month before this episode aired. He appeared in several episodes of season 1.
Coulson teaches at Alexander Pierce High School. Alexander Pierce was one of the main characters in Captain America: The Winter Soldier (2014).
A newspaper article in Phil Coulson's folder says, "Winslow Doctor Arrested for Subversion." While the headline suggests the doctor lives in a place called Winslow, the article says the man arrested is a doctor in Cleveland who was experimenting with altering human genetics. Though they don't release his name, Dr. Winslow is the new name given to Calvin Johnson (Daisy's father) played by Kyle MacLachlan after his mind is wiped by the TAHITI device at the end of Season 2.
In the Framework, the world is taken over by Hydra. This could be a nod to the Marvel Comic event Secret Empire in which Hydra rules the world and Captain America is a Hydra agent.
What If... is the sixteenth episode of the fourth season and the beginning of the Agents of HYDRA pod.