He denies the label of "Buddhist Comedian," but his podcast's humor frequently draws on high-concept Vajrayana metaphysics, and he commonly references the professional work of spiritual leaders such as Ram Dass and Chögyam Trungpa during conversations with guests.

Trussell also hosts a weekly meditation session and discussion of mindfulness practice for fans that subscribe to his work through Patreon.

[5] Among the guests that have been featured are Andrew Yang, Joe Rogan, Ram Dass, Amishi Jha, Dan Harmon, Joey Diaz, Tim Ferriss, Lou Barlow, Bert Kreischer, Alex Grey, Rick Doblin, Natasha Leggero, Graham Hancock, Abby Martin, Dr. Drew, Daniele Bolelli, Christopher Ryan, and comedian, podcaster Jessa Reed.

Select episodes of the show were adapted into the Netflix animated series The Midnight Gospel, directed by Pendleton Ward.

The show is a high-concept postmodern sci-fi sitcom with Trussell's podcast interviews inspiring story dialogue and animation added afterward.

[citation needed] Trussell has dated fellow comedians Mary Lynn Rajskub and Natasha Leggero, as well as model Cora Keegan.