After contemplating how to open his show, John discusses his parents' approach to nurturing their kids' creativity and his lack of trust in someone until he has heard them laugh.
Lurie recounts his cancer treatment and vertigo, while remembering an incident involving him reheating curry with a gas stove. He goes on to show more of his life at home on his undisclosed Caribbean island, enjoying rolling tires down hills, and with his housemates, and recounting the time he met Barry White, who said he was very fond of the Lounge Lizards' album Voice of Chunk.
Lurie discovers fragment of a tree that resembles an elephant trunk. He discusses his upbringing with his brother and their shared love of Little Walter, and John Coltrane. The background of the art design of the album cover of Voice of Chunk is discussed, with an elaborate tale of Lurie purchasing and photographing an eel. Lurie is, additionally, painting a piece called Elephant, revealed in the end credits.
Lurie discusses his thoughts on fame and what he had encountered in his life as a musician and actor: a casual meeting with Gore Vidal, partying with Rick James and Steve Rubell, mentoring Zach Galifanakis, his friendship with Anthony Bourdain, and his collaborations with Jim Jarmusch and Tom Waits.
Lurie recounts his times with his companion 'Leroy' around his village concerning various neighbors and townspeople whom they were convinced were mysteriously disappearing, one of them they nicknamed "The Chicken Man". He goes on to discuss his relationship with his mother, and their collective disgust with the registry of motor vehicles in Massachusetts. This ends with a live action/animated mashup of Lurie's artwork and surroundings among his song (alias Marvin Pontiac) 'My Little Garden Gnome' playing in the background.
Lurie recounts his friendship with a man named "Rudolph" on the remote island he lives on, and reminisces on their times together, before Rudolph's absence from his life. Lurie and Nesrin set out to reunite with Rudolph while enjoying the countryside. Lurie describes the local tree frogs he hears in their natural habitat and their musical coordination. Lurie wraps up the series discussing how, despite his battles with his illnesses, he happened to meet the series cinematographer Erik leading to a new series and a medium for him to showcase his work, yet just how uncomfortable it made him. The series ends with John Lurie successfully commandeering his drone for his show's introduction and welcoming the viewer to Painting with John. His collective artwork is showcased in the end credits.
