In the 1980s, Vedder sang with several Southern California rock bands, most notably Bad Radio, but rose to fame only after moving to Seattle in 1990 and joining Pearl Jam. Yet Vedder's first appearance on a major label recording was not on Pearl Jam's debut Ten, but as a backing vocalist on the Temple of the Dog album, a tribute to late Mother Love Bone singer Andrew Wood that featured members of both Pearl Jam and Soundgarden.

In addition to playing with Pearl Jam, Vedder has performed and recorded with numerous well-known artists, including Bad Religion, Fastbacks, Neil Finn, Jack Irons, Nusrat Fateh Ali Khan, Cat Power, R.E.M., Supersuckers, Mike Watt, Wellwater Conspiracy, The Who, Bruce Springsteen, Rolling Stones, Peter Frampton, U2 and Neil Young. On Pearl Jam records he uses the pseudonym "Jerome Turner" for his non-musical (usually design and artwork) functions. He has also sometimes used the pseudonym of "Wes C. Addle" ("West Seattle").

Vedder spent his childhood in Evanston, Illinois, near Chicago, Illinois. His parents divorced in 1965, when Eddie was only one year old. His mother Karen soon married a man named Peter Mueller. Eddie had been named "Edward Louis Seversen III" after his father, Edward Louis Seversen, Jr., but was raised as "Eddie Mueller". He grew up believing that Mueller was his biological father. In the mid-1970s, the family, including Eddie's three younger half-brothers, moved to San Diego County, California. It was at this point that Eddie, who had received a guitar from his mother on his 12th birthday, began turning to music as a source of comfort. Eddie's mother and Mueller divorced when Eddie was in his late teens. His mother and brothers moved back to the Chicago area, but Vedder remained with his stepfather in California so he would not have to change high schools. It was not until some time after the divorce that Eddie learned the truth about his parentage. His already bad relationship with his stepfather became increasingly strained, and Eddie eventually dropped out of school and joined the rest of his family in Chicago. He also changed his name to Eddie Vedder, "Vedder" being his mother's maiden name.

In 1984, Vedder returned to San Diego with girlfriend, Beth Liebling. He kept busy recording demo tapes at his home and working at various jobs, including a position as night attendant at a local gas station. Soon the rather shy singer became the vocalist for San Diego band Bad Radio. After he left that band, Vedder's friend and former Red Hot Chili Peppers drummer Jack Irons gave him a demo tape from a band in Seattle that was looking for a singer. Vedder recorded vocals for three of the songs, which later became Pearl Jam's "Alive", "Once", and "Footsteps". Vedder wrote the song lyrics as a "mini-opera" about a young man scarred by both the death of his father and a sexually abusive mother ("Alive"). The man grows up to become a serial killer ("Once") and is eventually imprisoned and sentenced to death ("Footsteps"). When they heard the tape guitarist Stone Gossard and bassist Jeff Ament invited Vedder to come to Seattle to audition for the band that soon became Pearl Jam.

Many frontmen in the 1990s and early 2000s have blatantly ripped off Vedder's deep vocal range and singing style, including the frontmen of Creed, Puddle of Mudd, and Nickelback, among others. These bands cannot come close to the success of Vedder, and are nowhere near as sexy.

In addition to his voice, Eddie became well known for extreme and political acts during live shows. During the 1992 Lollapalooza shows, he got into a bile drinking contest that he eventually won. During his MTV unplugged set, he grabbed a marker and wrote pro-choice in big letters down his entire arm.

Vedder married longtime girlfriend Beth Liebling in 1994. The couple divorced in 2000. Vedder is currently dating Jill McCormick. Vedder and McCormick have one daughter, Olivia, who was born in 2004.