Keep Trevor "Broom" Bruttenholm Alive
OK, this one may require a little bit of explaining. In the comic's first arc, Seed of Destruction by Mignola and John Byrne, Bruttenholm, the paranormal researcher who adopted Hellboy as his own son and was there when he entered our world, is killed by a frog monster as part of the story's inciting incident. In the 2004 film, he's murdered by Rasputin and Karl Ruprecht Kroenen as part of Rasputin's scheme (although he appears in a flashback in Hellboy II). Those are both touching, horrifying touches on their own--and they should be avoided.
As readers of the spin-off B.P.R.D. comics know, Bruttenholm had a ton of adventures before his death. Bringing that to the screen through either flashback or putting him in the field in the present would make this movie substantially different from any other Hellboy adaptation. Heck, even just keeping him alive long enough to give Hellboy a parent to talk to and have a bond with would be as welcome now as it was when DC Comics opted to keep Jonathan and Martha Kent alive in the post-Crisis era.
Don't Be afraid To Get Weird
When it comes to the more fantastical comic book adaptations, the Hollywood rule of thumb has historically been to sand things down to keep the film less costly and to be more appealing to a mass audience. See exhibit A: pretty much every X-Men film through X-Men: First Class. That sort of thinking is still present in some corners, but it's been largely thrown out thanks to the Marvel Cinematic Universe captivating audiences everywhere by using cutting-edge ILM effects and the financial resources of Disney to bring comic book costumes and characters look as accurate and cool as possible.
It's way too early to say what Rise of the Blood Queen will do with its budget, whatever that winds up being, but above all else, Marshall and his crew should remember that the universe of Hellboy is a weird, weird place. To stay true to Mignola's designs is one thing, but to honor his tone is another, and the best way to do that is to lean fully into the franchise's combination of weird monsters and crazy set pieces. The del Toro films had eye-popping sights like subway fights with immortal demon dogs, and the entrance to a robot army being hidden inside a living prehistoric stone sculpture guarded by a goblin with a truck flatbed for legs. For their part, the animated films had stuff like a kappa that looked like the Creature from the Black Lagoon and an ancient vampire seductress. As we mentioned previously, Hollywood's special effects are better than ever, so as long as the production sticks to Mignola's concepts, characters and most importantly, tone, it should all work out.