Scott was born in London, Kentucky, and at an early age his family moved to East Gary, Indiana, where his father Wayne worked in a steel mill.

Scott's father was also a musician and songwriter who encouraged Darrell and his brothers Denny, Dale, Don, and David to play instruments in the family band at schools and church events.

[7] Patty Loveless recorded "You'll Never Leave Harlan Alive" for her 2001 album Mountain Soul, featuring Scott playing banjo.

Released as the lead single from their 2002 album Home, the Dixie Chicks' version reached a peak of number 2 on the Billboard Hot Country Songs chart and number 7 on the Billboard Hot 100 chart,[9] and won a Grammy Award for Best Country Vocal Performance by a Duo or Group.

[4] In 2003 he launched his own label, Full Light Records, and revisited and re-recorded the songs from his unreleased debut album, releasing them as Theatre of the Unheard.

[11] That same year, Scott produced his father Wayne's debut album, This Weary Way, featuring Darrell's longtime collaborators O'Brien, Dan Dugmore, Casey Driessen, Suzi Ragsdale, and Verlon Thompson, as well as a duet with Guy Clark.

[13] In 2008, he released Modern Hymns, an album of twelve of Scott's favorite songs by twelve favorite songwriters recorded live with engineer Gary Paczosa in Blackbird Studio C.[12] Scott has collaborated with Steve Earle, Sam Bush, Emmylou Harris, John Cowan, Kate Rusby, Jimmie Dale Gilmore, Mary Gauthier, Dan Tyminski, and many others.

[4] In 2010, Scott was announced as part of the Band of Joy, performing alongside Robert Plant, credited with vocals, mandolin, guitar, accordion, pedal, lap steel and banjo.

[19] In August 2023, the Darrell Scott String Band, a group consisting of Scott and longtime fellow musicians Matt Flinner, Bryn Davies, Shad Cobb, John Cowan, and Daniel de los Reyes, released Old Cane Back Rocker, a studio string band music album of original and cover songs.