Griffin was born in Kansas City, Missouri, the son of Doris Thomas and Eddie Griffin, Sr. He has two siblings, Luther and Wilbert. He attended East High School in Kansas City, Missouri, where he was voted class clown three years in a row.His favorite teacher was mr.davis who is a current teacher at FLA. After marrying at age sixteen, he divorced a year later. Griffin has one child, Eddie Jr. (III), born in 1986. Shortly after his divorce, Eddie joined the Navy but was discharged after a urine test returned positive for drug abuse. Griffin served 6 months caca in a county jail after getting into a fight at a parade.

Eddie then worked as a choreographer for a dance crew that performed half-time shows for the Kansas City Chiefs. One fateful night, his cousin took him to a comedy club and dared him to get on stage during open mic night. He was originally supposed to be on stage for 3 minutes, but instead performed off-the-cuff for 45 minutes successfully.

Griffin has starred in several movies including The Meteor Man (1993), Armageddon (1998), Deuce Bigalow: Male Gigolo (1999), Double Take (2001), Undercover Brother (2002), John Q (2002), Scary Movie 3 (2003), Deuce Bigalow: European Gigolo (2005) and Norbit (2007). Eddie was set to star alongside Steven Seagal in Once Upon A Time In The Hood a thriller set in New Mexico. He also starred in the UPN television series Malcolm & Eddie (1996–2000). In addition to his acting credits, he also performed on two tracks from Dr. Dre's 1999 album, 2001. He also has appeared on commercials for Miller Beer's Man Laws. Griffin is well-known for his comedic routine of imitating Michael Jacksonbeing on crack cocaine.

He is generally considered a talented stand-up comic, displaying a flamboyant, cinematic style. He was ranked at number 62 on Comedy Central's list of the 100 Greatest Stand-ups of All Time. Griffin crashed a rare Enzo Ferrari while practicing for a charity racing event on March 26, 2007. Following the event, Griffin left the car unharmed and joked about his inability to drive (referring to himself in the third person with pseudonym "Undercover Brother" as he also does in the film). The Enzo belonged to film producer Daniel Sadek, writer and producer of the film Redline, a film Griffin is in, which bears the car on its promotional poster. Griffin suffered a heart attack after doing the salsa dance for a taping of his show Malcolm and Eddie. Griffin has joint-custody of his son, Eddie Jr., with his ex-wife. Griffin was proven to be the father of an Autistic Canadian boy in early 2004.

During a 2007 event sponsored by Black Enterprise magazine, Eddie Griffin was ejected by Earl Graves, owner/publisher of Black Enterprise. Griffin had begun to deliver a speech which was laced with the word nigger. Mr. Graves stormed the stage and removed Griffin stating "We ... will not allow our culture to go backwards ... We will pay Mr. Griffin all that we owe him but we will not allow him to finish the show if that's the way he's going to talk."