Although his parents were not involved in show business, Moe, his older brother Samuel, (who earned the nickname "Shemp" because of his mother's thick-accented mispronunciation of "Sam") and younger brother Jerome (Curly) all became world famous as part of the Three Stooges.

In school, Moe originally did quite well, aided by a prolific memory, able to quickly memorize anything. In later years, this helped him in his acting career, making memorizing his lines quick and easy. Moe loved reading, as his older brother Jack commented "I had many Horatio Alger books and it was Moe's greatest pleasure to read them. They started his imaginative mind working and gave him ideas by the dozen. I think they were instrumental in putting thoughts into his head to become a person of good character and to become successful."

Moe's largest problem, in his early years, was undoubtedly his hair. Although his "bowl-cut" hair cut is now world famous, as a child his mother refused to cut his beautiful hair, letting it grow to shoulder length. One day, he couldn't take his classmates' teasing any longer, snuck off to a shed in their backyard, and with the help of a friend and a mixing bowl, cut his hair. The hair style stayed with him for the rest of his life.

However, the allure of the stage started calling him, and the more he followed it, the worse he began doing in school. He began playing hooky from school in order to attend theater shows. Moe said, "I used to stand outside the theater knowing the truant officer was looking for me. I would stand there 'til someone came along and then ask them to buy my ticket. It was necessary for an adult to accompany a juvenile into the theatre. When I succeeded I'd give him my ten cents-that's all it cost-and I'd go up to the top of the balcony where I'd put my chin on the rail and watch, spellbound, from the first act to the last. I would usually select the actor I liked the most and follow his performance throughout the play"

Despite his decreasing attendance, Moe graduated from P.S. 163 in Brooklyn, but dropped out of Erasmus High School after only two months, the end of his formal education. To please his parents, he took a class in electric shop, but dropped out after a few months to pursue a career in show business.

He began by running errands for no fee at the Vitagraph Studios in Midwood, Brooklyn (currently the home of the CBS Soap, "As the World Turns"), where he was rewarded with bit parts in movies being made there. Unfortunately, a fire at the studios in 1910 destroyed copies of most of Moe's work done there. In 1909, he met a young man named Ted Healy, who would later become a major milestone in his life. For the time, though, Moe and Ted became good friends. In 1912, they both held a summer job working in Annette Kellerman's aquatic act as diving "girls."

Moe continued his attempts at gaining show business experience, by singing in a bar with his older brother Shemp (until their father put a stop to it), and in 1914 joining a performing troupe on a showboat for the next two summers. In 1922, he joined Ted Healy in a vaudeville routine, Ted Healy and his Racketeers - the group later changed its name to Ted Healy and his Stooges.

On June 7, 1925, Moe Howard married Helen Schonberger, a cousin of magician Harry Houdini, and truly lived happily ever after until his dying day. The next year, Helen pressured Moe to leave the stage, as she was pregnant and wanted Moe nearer to home. Moe attempted to earn a living in a succession of "normal" jobs, none of which were successful. He returned to working with Ted Healy afterwards.

By 1930, Ted Healy and his Stooges were on the verge of "the big time," and made their first movie, "Soup to Nuts" - featuring Ted Healy, and his four stooges - Moe Howard, Larry Fine, Shemp Howard, and Fred Sanborn for MGM. Shemp had not seen eye-to-eye with Healy, and left the group shortly after filming, in order to pursue an individual film career. Moe brought in his baby brother, Jerome ("Jerry" to his friends, "Babe" to Moe) as a replacement - after Healy had him shave off his mustache and hair, he took the stage name of "Curly." After a number of appearances in MGM films with Healy, in 1934, Ted Healy and his Stooges separated, with Healy pursuing his own career, and The Three Stooges (Fred Sanborn having previously left) began making short films at the Columbia film studio, where they stayed until 1957, making 190 films.

With Healy's departure, Moe's character assumed Healy's previous role of the aggressive, take-charge leader of the Three Stooges, short tempered and prone to slapstick violence against the other two stooges. In many ways, this was the antithesis of Moe Howard's true self; he was quiet, loving, and generous to his friends and family. In fact, he was one of those men who had problems showing affection — instead, he would shower his loved ones with gifts, increasing in quantity and expensiveness over time as his fortunes improved. He was also foresighted, and invested the money made from his film career very wisely, allowing him to retire in luxury. He also, trying to ensure a similar future for his high-spending fellow Stooges (Curly would go nightclubbing and Larry was an avid gambler), got them to agree to allow him to take a portion of their salaries to invest for their old age.

In 1934, they released their first Three Stooges, short subject for Columbia, Woman Haters, where their characters where not quite finalized. This was changed by their next film, Punch Drunk, the only short film that was written entirely by the Three Stooges. Their next short, Men in Black, was their first and only film to be nominated for an Academy Award (with the classic catchphrase, "Calling Dr. Howard, Dr. Fine, Dr. Howard"). They continued making short films at a record pace, such as Three Little Pigskins (with a very young Lucille Ball), Pop Goes the Easel, Hoi Polloi (where two professors try to solve a bet by turning the Three Stooges into gentlemen), and many others.

In the 1940s, the Three Stooges become slightly political, making several anti-Nazi movies, including You Nazty Spy (1940), (Moe's favorite Three Stooges film), I'll Never Heil Again (1941), and They Stooge to Conga (1943). Moe's dead-on impression of Adolf Hitler augmented these shorts. Though unusual in their political commentary, these shorts were often hilarious as well.

By the end of World War II, Moe's brother Jerome (Curly) had been diagnosed as having extreme hypertension, a retinal hemorrhage and obesity. The next year, Curly suffered a massive stroke during the filming of Half-Wits Holiday. Although Moe made certain that his baby brother received the best medical care, he had him replaced in the Three Stooges by Shemp, who returned to the group until Curly was well enough to rejoin the Stooges. Although he had recovered enough to appear in Hold That Lion (1947) in a cameo appearance (the only Three Stooges film to contain all four Stooges: Moe, Larry, Curly, and Shemp), he suffered a series of strokes, leading to his early death in 1952.

The Three Stooges continued to make short films for Columbia into the 1950s—the era of television. In 1955, Moe's brother Shemp Howard died of a heart attack, necessitating the need for another stooge. Existing footage enabled the Stooges to complete the films that they had been working on until Moe hired Joe Besser, who worked with Moe and Larry making shorts until 1959. The making of shorts had come to an end, but with Columbia's sale of the library of short films to television, the Three Stooges quickly gained a new audience of young fans, prompting Columbia to star them in several feature-length movies - Have Rocket, Will Travel (1959), Snow White and the Three Stooges (1961), The Three Stooges Meet Hercules (1962), The Three Stooges In Orbit (1962), The Three Stooges Go Around the World in a Daze (1963), and The Outlaws IS Coming (1965). By this time, Joe DeRita (dubbed "Curly-Joe", due to his resemblance to former stooge Curly Howard) had stepped into the "third stooge" role, as Joe Besser had bowed out.

Moe, Larry and Curly-Joe continued to make live appearances, many notable "guest appearances", notably in It's a Mad Mad Mad Mad World (1963) — as firemen! — and 4 for Texas (1963). The boys tried their hand at a children's cartoon show entitled The New 3 Stooges, with the cartoons sandwiched between live action segments of the boys. However, by 1965, it was clear that the trio were not immune to age. They were simply getting too old to do slapstick comedy.

Moe's professional life slowed down dramatically, although he still did minor roles and walk-on bits , television appearances ("Here's Hollywood", "Toast of the Town", "Masquerade Party", and several appearances on "The Mike Douglas Show"). There was also the Stooges final film, Kook's Tour (1970), which was essentially an early "reality TV" show of Moe, Larry and Curly-Joe, out of character, touring the country and interacting with fans.

Moe Howard died of lung cancer on May 4, 1975 in Los Angeles, California, USA. His remains are interred at Hillside Memorial Park, Culver City, California.