Uggie was put down at the age of 13 due to prostate tumour.
Witherspoon, who worked with the Jack Russell terrier in her 2011 film "Water for Elephants", took to Instagram and said he was a "special soul", reported Entertainment Weekly.
"RIP to my canine friend Uggie. I worked with him on Water for Elephants. What a special, sweet soul," she wrote alongside the photo and included a dog emoticon with the post.
"Affectionate thoughts for my exceptional partner. Rest In Peace. Uggie...," he wrote.
Uggie won the Palm Dog Award at the 2011 Cannes Film Festival for his work in "The Artist". He did all his stunts in the movie and was the first canine to have his paw prints on the Hollywood Walk of Fame.