The Dark Shadows actor revealed that he took inspiration from the former American president when portraying the character in Tim Burton's 2005 movie Charlie and the Chocolate Factory.
Depp said he had considered how Bush might act if he was high when he thought about how to carry out the role.
Speaking to talkshow host Ellen DeGeneres, he said: "Certain ingredients you add to these characters - Willy Wonka, for example, I imagined what George Bush would be like…incredibly stoned, and thus was born my version of Willy Wonka."
Depp continued: "[Edward] Scissorhands was a combination. It was the idea of a newborn seeing things for the first time and also a dog that I had, and the unconditional love and purity in my dog.
"Anywhere that you can find a moment of irreverence or absurdity, I'll stick it right in there - sometimes to the dismay of the director."
Depp's Dark Shadows co-star Michelle Pfeiffer admitted that Depp has been on her list of crushes for a while, saying : "He was on my bucket list but I was leaving [him] out to work with!"
Pfeiffer's comment caused Depp to reply: "It's getting warm in here!"
Dark Shadows opens on Friday, May 11 in the UK and the US.