Warning: Spoilers for the series finale of Agents of S.H.I.E.L.D. are ahead.
While the now cancelled Marvel Studios shows on Netflix (Daredevil, Jessica Jones, Luke Cage) have kept their distance from big screen MCU events, it's a different story for ABC shows like Agents of S.H.I.E.L.D. and Agent Carter. Both ABC series were lead by a character who originated in the Marvel films to begin with (Clark Gregg's Phil Coulson and Hayley Atwell's Peggy Carter), and both have had characters cross over from the big screen and back (Samuel L. Jackson's Nick Fury and Cobie Smulders' Maria Hill, for starters). Bit characters from Thor and Captain America have shown up on Agents of S.H.I.E.L.D. (hello, Jaimie Alexander as Lady Sif!) and the series finale hinted at Phase 4, a.k.a. the set of MCU movies that includes The Eternals and Black Panther 2, in more ways than one. Just when you think certain characters have been forgotten, the MCU powers that be pulls out their metaphorical rolodex and ring someone up for a surprise cameo — like the one Agent Carter actor James D'Arcy had in Avengers: Endgame.
The aforementioned Netflix shows were also contractually unable to "release" the rights to the characters for a number of years after their respective series finales, and who knows if we'll ever see characters from other MCU-set shows like Runaways or Cloak and Dagger again. But since S.H.I.E.L.D. aired on ABC, which is owned by Disney, there isn't likely to be any red tape keeping Marvel from hiring S.H.I.E.L.D. actors and telling stories with these characters. On the other hand, most of the Agents of S.H.I.E.L.D. cast members have been playing their parts for seven years now. We should let them go if they want.
Most importantly, we don't know anything yet. The future of the MCU is murky on the details. So let's temper our expectations. Here's what is most likely to happen. And a few things that are pretty damn unlikely.
Who Will Probably Come Back To The MCU: Coulson
Captain Marvel proved that the MCU is still down to extend the big screen invitation to Gregg. Seven deaths can't keep Agent Coulson away. Even though the LMD Coulson reserved the right to "switch off" after the finale, there are always new chapters of Marvel history to explore with him via flashbacks, and the ever-looming possibility of the multiverse.
Who Could Come Back To The MCU: Daisy Johnson
The most likely crossover candidate is Daisy Johnson, a.k.a. Quake (Chloe Bennet). She's a bonafide Avenger in the comics and Bennet has actually already reprised her role in the animated series Marvel Rising on Disney+. The gauntlet has absolutely been thrown. At the end of Agents of S.H.I.E.L.D. she is essentially starting up S.W.O.R.D. from the comics — which is basically S.H.I.E.L.D. in Space. She seems primed for future Marvel adventures.
Next in line, in my opinion, are Natalia Cordova-Buckley and Henry Simmons as Yo-Yo Rodriguez and Alphonso "Mack" Mackenzie — primarily because they were established characters in Marvel comics before Agents of S.H.I.E.L.D. and are active agents at the end of the finale. Plus, Mack's "situation in Moscow" alluded to in the finale is almost certainly the events of the Black Widow movie. Unfortunately we'll have to wait to find out if he's actually in it — which I kind of doubt, but it's a cool finale Easter Egg either way.
Everyone Who Almost Certainly Won't Come Back To The MCU
A big "maybe" in my book is Melinda May (Ming-Na Wen). On one hand, she's an original S.H.I.E.L.D. character and therefore might not fit in to any planned MCU adaptations of comic book arcs. On the other hand, May is a badass and Wen is such a Disney staple at this point (she's in The Mandalorian and is the original voice of Mulan, NBD) that they'd be fools to let her go. Pull an Indiana Jones and get her to take a sabbatical from her teaching gig at the Coulson Academy for another mission. Easy!
Unfortunately, I don't really see a world in which FitzSimmons (Iain De Caestecker and Elizabeth Henstridge) return to the MCU after the series finale — and after everything Jemma and Leo have been through on Agents of S.H.I.E.L.D. who can blame them? Let them be retired parents in peace. The same goes for minor-ish characters like Grant Ward (Brett Dalton), Deke (Jeff Ward), Daniel Sousa (Enver Gjokaj), Lance Hunter (Nick Blood), Lincoln (Luke Mitchell), and Enoch (Joel Stoffer). Their stories are over.
Were I to make a wish on the the star adorning Captain America's uniform, I would personally love to see Adrianne Palicki return to the MCU as Bobbi Morse/Mockingbird and start up the West Coast Avengers from the comics, or maybe pop into the Hawkeye series as Clint Barton's (Jeremy Renner) canonical ex-wife, but I'm not getting my hopes up too high.
The way that Coulson's team split up at the end of Agents of S.H.I.E.L.D. did double duty as a satisfying ending for each of the characters fans have grown to love over the years and setting up possible future adventures. It may be a spy's goodbye for now, but you never know what's around the corner.