Goldberg was born July 4, 1883, in San Francisco, California, to Jewish parents Max and Hannah (Cohen) Goldberg. He was the third of seven children, three of whom died as children (older brother Garrett, younger brother Walter, and younger sister Lillian also survived).

Goldberg's Father was a San Francisco police and fire commissioner, who encouraged the young Reuben to pursue a career in engineering. Rube graduated from the University of California, Berkeley in 1904 with a degree in Engineering and was hired by the city of San Francisco as an Engineer for the Water and Sewers Department. After six months he resigned his position with the city to join the San Francisco Chronicle where he became a Sports Cartoonist. The following year, he took a job with the San Francisco Bulletin, where he remained until he moved to New York City in 1907, finding employment as a Cartoonist with the New York Evening Mail.

In 1909 Goldberg invented the "Foolish Questions" game based on his successful cartoon by the same name. The game was published in many versions from 1909 to 1934.

The popularity of Goldberg's cartoons was such that the term "Goldbergian" was in use in print by 1915, and "Rube Goldberg" by 1928. "Rube Goldberg" appeared in the Random House Dictionary of the English Language in 1966 meaning "having a fantastically complicated improvised appearance", or "deviously complex and impractical." The 1915 usage of "Goldbergian" was in reference to Goldberg's early comic strip Foolish Questions which he drew from 1909 to 1934, while later use of the terms "Goldbergian", "Rube Goldberg" and " Rube Goldberg machine" refer to the crazy inventions for which he is now best known from his strip The Inventions of Professor Lucifer Gorgonzola Butts, drawn from 1914 to 1964.

Goldberg married Irma Seeman on October 17, 1916. They lived at 98 Central Park West in New York City and had two sons named Thomas and George.

Goldberg was syndicated by the McNaught Syndicate from 1922 until 1934.

Rube Goldberg wrote a feature film featuring his machines and sculptures called Soup to Nuts, which was released in 1930 and starred Ted Healy and the pre-Curly Howard version of The Three Stooges.

A prolific Artist, Goldberg produced several cartoon series simultaneously, including Mike and Ike (They Look Alike), Boob McNutt, Foolish Questions, What Are You Kicking About, Telephonies, 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. The cartoons that brought him lasting fame involved a character named Professor Lucifer Gorgonzola Butts. In that series, Goldberg drew labeled schematics of the comical "inventions" that would later bear his name.

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).

Goldberg is best known for a series of popular cartoons depicting complicated gadgets that perform simple tasks in indirect, convoluted ways, giving rise to the term Rube Goldberg machines for any similar gadget or process. Goldberg received many honors in his lifetime, including a Pulitzer Prize for his political cartooning in 1948 and the Banshees' Silver Lady Award in 1959.

In the late 1960s and early 70s, educational shows like Sesame Street, Vision On and The Electric Company routinely showed bits that involved Rube Goldberg devices, including the Rube Goldberg Alphabet Contraption, and the What Happens Next Machine.

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."

Also in the Final Destination film series the characters often die in Rube Goldberg-esque ways. In the film The Great Mouse Detective, the villain Ratigan attempts to kill the film's heroes, Basil of Baker Street and David Q. Dawson, with a Rube Goldberg style device. The classic video in this genre was done by the Artist duo Peter Fischli & David Weiss in 1987 with their 30-minute video "Der Lauf der Dinge" or "The Way Things Go".

Both board games and video games have been inspired by Goldberg's creations, such as the 60's board game Mouse Trap, the 1990s series of The Incredible Machine games, and Crazy Machines. The Humongous Entertainment game Freddi Fish 2: The Case of the Haunted Schoolhouse involves searching for the missing pieces to a Rube Goldberg machine to complete the game.

Goldberg's work was commemorated posthumously in 1995 with the inclusion of Rube Goldberg's Inventions, depicting his 1931 "Self-Operating Napkin" in the Comic Strip Classics series of U.S. postage stamps.

In 1999, an episode of The X-Files was titled "The Goldberg Variation". 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.

Honda produced a video in 2003 called "The Cog" using many of the same principles that Fischli and Weiss had done in 1987.

In 2005, the American alternative rock/indie band The Bravery released a video for their debut single, "An Honest Mistake," which features the band performing the song in the middle of a Rube Goldberg machine.

The 2010 music video "This Too Shall Pass – RGM Version" by the rock band OK Go features a machine that, after four minutes of kinetic activity, shoots the band members in the face with paint. "RGM" presumably stands for Rube Goldberg Machine.

2012 The CBS show Elementary features a machine in its opening sequence.

Rube Works: The Official Rube Goldberg Invention Game, the first game authorized by The Heirs of Rube Goldberg, was published by Unity Games (the publishing arm of Unity Technologies) in November 2013.

2014 The Web Series, "Deadbeat," on Hulu features an episode titled, "The Ghost in the Machine," which features the protagonist, Kevin, helping the ghost of Rube Goldberg complete a contraption that will bring his grandchildren together after making a collection of random items into a machine that ends up systematically injuring two of his grandchildren so they end up in the same hospital and finally meet.