The LA-based Razzies, which honor the year's worst Hollywood films, have given Murphy five nods - the most an individual has received in one year.
He plays three characters in the film about a man who meets his ideal woman while engaged to a battleaxe.
Lohan got two nods for playing two characters who may be the same person.
Both movies are up for worst film.It is quite a turnaround in Murphy's fortunes, as he was up for an Oscar last year for Dreamgirls. He shares a worst screenplay nomination for co-writing Norbit.
"We decided that each of his characters was so offensive that he deserved individual nominations," said Razzies founder John Wilson.
He added that Lohan, whose characters are a small-town girl abducted by a psychopath and an alter-ego stripper who's missing body parts, got more votes than any other actor since Sofia Coppola in The Godfather Part III.
"I Know Who Killed Me is the most fabulously brainless movie since Showgirls, which Razzie voters picked as the worst movie of the 1990s," said Mr Wilson.
"By the end of it, you still don't know what happened. Are they twins or aren't they? Did she imagine it? Can I please have my hour and 50 minutes back?"
The other worst-picture nominees were Bratz, a live-action film based on the childrens' dolls; Daddy Day Camp, with Cuba Gooding Jr starring in the sequel to Murphy's Daddy Day Care; and I Now Pronounce You Chuck & Larry, Adam Sandler and Kevin James' comedy about firefighters posing as a gay couple.
Sandler and Gooding were both up for worst actor along with Nicolas Cage for Ghost Rider and Jim Carrey for The Number 23.
The four stars of Bratz shared a nomination for worst actress, along with Jessica Alba for three films - Awake, Fantastic Four: Rise of the Silver Surfer and Good Luck Chuck.
24 star Elisha Cuthbert was nominated for Captivity while Diane Keaton got a nod for Because I Said So.
The Razzie nominations came out a day before the Oscar nominations, and the awards are held on 23 February, the day before the Oscars.
