Southern Comfort is used in the creation of many popular cocktails, including Alabama Slammer, Red Death, Red Devil, Crash & Burn, '57 Chevy, Sloe Comfortable Screw, SoCo Hurricane, The Princess Peach, Slo Sunrise, Rickstasy, SocoCola, SoCoCello, SoCo-LoCo, SoCo Manhattan, Blind Andy, SoCo Andy, Steamboat and Funky Cold Medina. Southern Comfort and club soda make a drink called An Old Woody.

One of the earliest Southern Comfort-based cocktails to be marketed was the Scarlett O'Hara, concocted in tribute to the release of the film adaptation of 'Gone with the Wind' in 1939. The mixture includes Southern Comfort, cranberry juice, and fresh lime.

Furthermore, in Ireland, Southern Comfort is often mixed with Red Lemonade (a type of soft drink popular in Ireland). This is known as a Southy and Red (or Suddy 'n' Red in Dublin).