[7] In 1911, he built the R. L. Goldberg Building at 182–198 Gough Street, San Francisco, for his widowed father to live in, as well as to collect rental income.

During World War II, as each of his sons headed off to college, Goldberg insisted that they change their surname because of antisemitic sentiment toward him stemming from the political nature of his cartoons.

Goldberg's father was a San Francisco police and fire commissioner,[10] who encouraged the young Reuben to pursue a career in engineering.

[17] Some of these cartoons include Mike and Ike (They Look Alike), Boob McNutt, Foolish Questions,[12][18] What Are You Kicking About,[19] Telephonies,[20] Lala Palooza, The Weekly Meeting of the Tuesday Women's Club, and the uncharacteristically serious soap-opera strip, Doc Wright, which ran for 10 months beginning January 29, 1933.

[21] The cartoon series that brought him lasting fame was The Inventions of Professor Lucifer Gorgonzola Butts, A.K., which ran in Collier's Weekly from January 26, 1929, to December 26, 1931.

In that series, Goldberg drew labeled schematics in the form of patent applications of the comically intricate "inventions" that would later bear his name.

[24] From 1938 to 1941, Goldberg drew two weekly strips for the Register and Tribune Syndicate: Brad and Dad (1939–1941) and Side Show (1938–1941), a continuation of the invention drawings.

[7]: 305 The corresponding term in the UK was, and still is, "Heath Robinson", after the English illustrator with an equal devotion to odd machinery, also portraying sequential or chain reaction elements.

[32] In 1998, Justice Scalia remarked in a dissent in a habeas case that "Rube Goldberg would envy the scheme the Court has created.

"[33] Rube Goldberg wrote the first feature film for the pre-Curly Howard version of The Three Stooges called Soup to Nuts, which was released in 1930 and starred Ted Healy.

In the 1962 John Wayne movie Hatari!, an invention to catch monkeys by character Pockets, played by Red Buttons, is described as a "Rube Goldberg."

Among these are Flåklypa Grand Prix, Looney Tunes, Tom and Jerry,[36] Wallace and Gromit, Pee-wee's Big Adventure, The Way Things Go, Edward Scissorhands, Back to the Future, Honey, I Shrunk the Kids, The Goonies, Gremlins, the Saw film series, Chitty Chitty Bang Bang, The Cat from Outer Space, Malcolm, Hotel for Dogs, the Home Alone film series, Family Guy, American Dad!, Casper, and Waiting...

The episode intertwined characters FBI agents Mulder and Scully, a simple apartment super, Henry Weems (Willie Garson) and an ailing young boy, Ritchie Lupone (Shia LaBeouf) in a real-life Goldberg device.

The iCarly (2007) episode iDon’t Want to Fight, Spencer built a Rube Goldberg Machine to feed his fish.

The Suite Life on Deck episode A London Carol, Cody built a Rube Goldberg Machine to help Zack wake up at six a.m.

The 2012 Discovery Channel show Unchained Reaction pitted two teams against each other to create an elaborate Rube Goldberg machine.