Queen Chrysalis is powered by love, yet she is defeated by it.
Sweetie Belle even lampshades how ironic life can get in "One Bad Apple" when they realize they've resorted to bullying to get back at a formerly bullied bully who was only bullying them to avoid getting bullied herself.
Meta Example: All but one of the American voice actors for the main characters are actually Canadian, and the one American VA is Canadian-born and records all her dialogue in Los Angeles.
"Weird Al" Yankovic guest-voiced a character on the show named Cheese Sandwich. Weird Al himself is a vegan.
Twilight Sparkle is the Princess of Friendship, yet she has a mental disorder heavily implied to be autism, a social learning disability.
Discord is an incredibly powerful Mad God who is constantly one step ahead of his opponents... and loses repeatedly when he assumes that their very simple tactics - which he sees right through - couldn't possibly work since he sees them coming. Celestia and Luna, Twilight Sparkle, and Fluttershy (twice) all defeat him by methods he knew they would try, but completely discounted.
Diamond Tiara's mother Spoiled Rich berates her for losing the class president election to "that transplant from Trottingham", referring to Pipsqueak, and adds it's worse to lose to "blank flanks", referring to the Cutie Mark Crusaders which Diamond herself had been calling for five straight seasons; Pipsqueak, whom she lost to, is a blank flank himself.
The fake clones of the Mane Six created by Chrysalis were to use the Elements against them and destroy them, but once they find the Elements it's the clones that get destroyed. In a similar manner, the clones are born from trees, yet they are killed by one.
Chancellor Neighsey is against the idea of non-pony creatures involving at the School of Friendship because he thinks they'll use what they learned against Equestria; Cozy Glow, a pony, is the one who tries to use said knowledge to take over Equestria, while the non-pony creatures are who foil her plan.