Uncle Grandpa originated from an animated short Peter Browngardt first pitched to Cartoon Network in 2006, which was later produced in 2008 and aired online in 2009 as part of The Cartoonstitute.

The series is a spin-off of Secret Mountain Fort Awesome, which itself was a spin-off of the original Cartoonstitute short, making Uncle Grandpa a second-generation spin-off.

Although Secret Mountain Fort Awesome was not well received and was put on hiatus in February 2012, it won the Crystal Award for Best Television Production at the Annecy International Animated Film Festival, becoming the first US-based production to do so, which helped boost Browngardt's profile and get Uncle Grandpa greenlit.

Creator Peter Browngardt based the title character on the eccentric relatives who would visit his large family of eight children growing up, as well as on aspects of his own personality.

The character's redesign by John Kricfalusi, creator of The Ren & Stimpy Show, was cited as another factor that helped the show get greenlit as a series.

Creator Peter Browngardt himself voices the title character, Uncle Grandpa.

Former NBA star Shaquille O'Neal voiced himself as an old friend of Uncle Grandpa in the episode 'Perfect Kid', helping him fight a cyborg by combining with the audience like a giant robot.

The character Akira in the episode 'Big in Japan' is named after Akira Ifukube, the Japanese composer best known for scoring several entries in the Godzilla franchise.

The character Xarna, She-Warrior of the Apocalypse, is a parody of Xena from Xena: Warrior Princess.

A faux Cartoon Network ad for a fictional spin-off called 'Uncle Grandpa Babies' first appeared within the 2014 episode 'Grounded' and jokingly claimed to be made by the creators of Adventure Time and Steven Universe; a full episode based on the concept aired a year later in 2015.

A crossover special with Steven Universe titled 'Say Uncle', conceived by Steven Universe creator Rebecca Sugar, aired as part of that show's second season in April 2015 and was viewed by nearly two million people.

The episode 'Guest Directed Shorts' featured segments directed by guest animators M. Wartella (Superjail!, Mad), Pendleton Ward (creator of Adventure Time), and stop-motion artist Max Winston, whose claymation short was nominated for best television production at the 2015 Annecy Film Festival.

The show's pilot was nominated for a Primetime Emmy Award in 2010 for Outstanding Short-Format Animated Program, and the series itself won an Emmy in 2014 for Nick Edwards' work in Outstanding Individual Achievement in Animation.

Retrospective reviews of the series became more positive after the release of Browngardt's later show Looney Tunes Cartoons, with critics and viewers praising Uncle Grandpa's concept, humor, and deranged animation in hindsight.