Ennis has played roles in Malcolm in the Middle and played a writer for the fictitious comedy show at the center of Studio 60 on the Sunset Strip. He also played a part in the YouTube channel RocketJump's Video Game High School as Kimberly Swan's father Kenneth Swan. In 2007, Ennis took a small part in the film Zodiac as Terry Pascoe, protégé of the handwriting expert Sherwood Morrill. He portrayed Kenneth Swan in the web series Video Game High School.
In July 2006, Ennis joined with musician and filmmaker Andrew Jon Thomson to form a cowboy harmony western comedy musical group named Saddle Pals, in the spirit of 1930s movie singing cowboy groups such as Sons of the Pioneers and contemporaries such as Riders in the Sky.
He is also an acting teacher, having taught for several years at the Lee Strasberg Theatre Institute in Los Angeles. In the fall of 2007, John Ennis became the "Z" for a series of Wheel of Fortune commercials to celebrate the 25th anniversary of the show.In 2015, he starred in commercials for Smith & Forge hard cider and Pur water.