In 2006 Trucks began a studio collaboration with JJ Cale and Eric Clapton called The Road to Escondido and performed with three bands in 17 countries that year.

Trucks and his wife, Susan Tedeschi, combined their bands to form the Soul Stew Revival in 2007, and performed at the Bonnaroo Music Festival in June 2008.

[14][15] On January 8, 2014, Trucks announced that he and fellow guitarist Warren Haynes planned to leave the Allman Brothers Band at the end of 2014.

[16] That band announced its retirement, with Trucks playing as a member through their final show on October 28, 2014, at the Beacon Theatre in New York City.

Trucks credits guitarist Duane Allman and bluesman Elmore James as the two slide guitarists who influenced his early style, but he has since been inspired by John Lee Hooker, Ali Akbar Khan,[17] Howlin' Wolf, Albert King, Miles Davis, Sun Ra, John Coltrane, Charlie Parker, Django Reinhardt, Charlie Christian, Wayne Shorter, Toy Caldwell, Johnny Winter, Freddie King and B.B.

"[25] Trucks plays guitar in an open E tuning,[26] using his signature glass slide by Dunlop, modeled off of an old Coricidin bottle but without the seam.

[27] In 2006, two vintage (1965 and 1968) Fender Super Reverb amplifiers, a Hammond B-3 organ, two Leslie speaker cabinets, and a Hohner E-7 clavinet were stolen from Trucks and later recovered by the Atlanta Police Department.

A 2006 article in The Wall Street Journal described him as "the most awe-inspiring electric slide guitar player performing today".

[30] In 2009, Ernest Suarez of The Washington Post described Trucks' guitar style as "notes and chords that soar, slice, and glide, sounding like a cross between Duane Allman on a '61 Gibson Les Paul and John Coltrane on tenor sax".

[34][35] On February 21, 2012, Derek Trucks and his wife joined other blues musicians for a performance at the White House for President Obama and his guests.