Well, everyone else is doing it, so why not me too?
My predictions are based on the assumption that the theme of Season 6 will be The Guardians of Harmony, which has been spoiled by recent trademark applications by Hasbro. These aren't all necessary 'predictions', there is an element of a 'wish list' too.
- Pony versions of the Crystal Prep Shadowbolts will be regular secondary characters as Twilight's personal guardsponies; Flash Sentry will be their commander and the writers will enjoy trolling us by giving him an extremely adversarial relationship with Twilight Sparkle;
- The season opener will include Starlight Glimmer having a significant role for a third two-parter and then she will become an very occasional secondary character with possibly only one more episode (which may be a focus on recent events in Our Town, which has either only minimal involvement of the Mane Six or even none at all);
- Sunset Shimmer will visit Equestria as part of her research into how magic works in the human world; this will be a three-character focus with Twilight, Sunset and Spike and will address some of Sunset's Equestrian past; depending on run-time or if they choose to stretch it to a double-length (a bit like the pairing of Canterlot Boutique and Rarity Investigates); this may include cameos from Twilight's Canterlot friends like Minuette and Moon Dancer.
- The Cutie Mark Crusaders will have at least two adventures associated with helping somepony find out what their cutie marks really mean; Diamond Tiara will debut as the group's regular fourth member;
- A season-length arc, like Season 4, will have the Mane Six each having individual adventures with their Shadowbolt counterpart as sidekick (Twilight's counterpart being Flash);
- Rainbow Dash will become a full Wonderbolt;
- Flash and the Shadowbolts will have a focus episode of their own;
- Cadance's foal will be born in the season finale which will also include the return of Chrysalis and the Changelings as a true time-line villain group; the episode will have a major action sequence at the end in which the nature of the 'Guardians of Harmony' will be fully revealed.
- The finale may include a hook or two for the Big Pony Movie although, because Hasbro wants the BPM to be stand-alone as far as is possible, it won't be necessary to see the finale to understand the movie.
Bonus Predictions (Equestria Girls 4 - Legends of Everfree):
- The human version of Starlight Glimmer will be the sixth member of the Crystal Prep Shadowbolts who may be antagonists (although not villains) in the film, due to the manipulations of Principal Cinch, who will be the real villain;
- The main plot of the film will be a 'race' of sorts between Canterlot High and Crystal Prep to uncover the truth behind an ancient myth regarding the Human world's version of the Everfree Forest and, consequently, come to a clearer understanding of this world's magic;
- Flash Sentry and Sci-Twi will be in an awkward friend-zone relationship;
- At least at one point, the HuMane Seven will dress up in garish superhero costumes designed by Rarity.