
McCain graduated from Christ Church Episcopal School in Greenville, South Carolina,[2] and briefly attended both the College of Charleston and Coastal Carolina University. Longtime touring friends with Hootie and the Blowfish, the Edwin McCain band signed with the same label, Atlantic Records. In 1994, he recorded his first major-label album, Honor Among Thieves under the Lava Records imprint (Matchbox Twenty, Kid Rock and Jewel). The record was then released in 1995. His second album, Misguided Roses, spawned "I'll Be", a major hit single in 1998. This song also is featured on the charitable album, Live in the X Lounge, along with a live version of "Solitude". It was also featured in the 2000 drama television show, Higher Ground, as well as the 2004 teen flick, A Cinderella Story. Summer of 1999 marked the arrival of McCain's third album, Messenger, which included a second Top 40 hit, the Diane Warren-penned "I Could Not Ask For More." Produced by Matt Serletic (Matchbox Twenty, Collective Soul) and Noel Golden, Messenger was recorded at Tree Sound Studios and Southern Tracks in Atlanta as well as Record Plant Studios in Los Angeles. "I Could Not Ask For More" was also featured on the soundtrack for the 1999 film Message in a Bottle.

Mid-2004 saw the arrival of his first studio album in three years, titled Scream & Whisper, which was released on another indie label, DRT Entertainment. Later that year, McCain made time in his tour schedule to run the 35th annual New York City Marathon. In an interview in the August 2004 issue of Runner's World, McCain said of training on the road: "You just pick your spots. One of the things that comes in handy depends on how far away the hotel is from the venue. ... For example, the other day the hotel was five miles away from the club where I was performing, so once we got to the club and got sound checked I threw on my running clothes, then ran back to the hotel. Little things like that help." In late 2004 McCain released his second DVD, Tinsel and Tap Shoes. It was his first live concert DVD, recorded at The House of Blues in Myrtle Beach, South Carolina.

On May 17, 2009, McCain performed on board the USS John C. Stennis, while the carrier was on a Western Pacific deployment in the vicinity of Guam. The next year saw the release of The Best of Edwin McCain, a 20-year career retrospective that included a cross-section of material as well as a new single, "Walk With You" (produced by Don Was.) McCain's 10th album, Mercy Bound, was released August 30, 2011, on 429 Records. Reuniting McCain with collaborator Maia Sharp, who also had production credits,Mercy Bound features additional artistic input from Angie Aparo, Mark Addison and Anders Osborne, as well as guitar work from Warren Haynes. McCain is also a ship restorer, as seen on the current Animal Planet TV series Flipping Ships. On January 22 2017, McCain sang the American National Anthem at Gillette Stadium for the AFC Championship Game between the New England Patriots and Pittsburgh Steelers.