His first flirtation with the film industry was when he served as a contractor to Hollywood studios, soundproofing production stages during the transition from silent pictures to sound. The company he owned with his brother went bankrupt when its financial backing failed in early days of the Great Depression. Not yet 21, Todd had lost over $1 million (equivalent to about $14,649,402 in today's funds). Having married the former Bertha Freshman on February 14, 1927, he was the father of an infant son and had no home for his family. Todd's subsequent Business career was volatile, and failed ventures left him bankrupt many times.

During the 1933-1934 Century of Progress Exposition in Chicago, Todd produced an attraction called the "Flame Dance". In this number, gas jets were designed to burn part of a dancer's costume off, leaving her naked in appearance. The act attracted enough attention to bring an offer from the Casino de Paree nightclub in New York City. Todd got his first taste of Broadway with the engagement and was determined to find a way to work there.

Todd's Broadway success gave him the nerve to try taking on showman Billy Rose. Todd visited Grover Whalen, President of the 1939 New York World's Fair, with a proposal to bring the Broadway show to the Fair. Whalan, eager to have the show at the fair, covered Todd's Broadway early closing costs. Rose, who had an exclusivity clause in his fair contract, met Todd at Lindy's, where Rose learned his contract covered new forms of entertainment only. To avoid any head-to head competition, Rose quickly agreed to promote Todd's production along with his own.

Todd floated the idea of holding the 1945 Major League Baseball All-Star Game in newly liberated Berlin. Although baseball's new commissioner Happy Chandler was reportedly "intrigued" by the idea, it was ultimately dismissed as impractical. The game was finally cancelled due to wartime travel restrictions.

At age 17, Todd married Bertha Freshman in Crown Point, Indiana, on Valentine's Day 1927. He had been interested in Freshman since age 14, but needed to develop confidence before even asking her out. In 1929, the couple's son, Mike Todd, Jr., was born. The death of his father in 1931 was a turning point for Todd; he decided to change his name to Mike Todd on the day of his father's death. Todd's wife, Bertha, died of a pneumothorax (collapsed lung) on August 12, 1946, in Santa Monica, California, while undergoing surgery at St. John's Hospital for a damaged tendon in her finger. Todd and his wife were separated at the time of her death; less than a week before Freshman's death, he had filed for divorce.

On July 5, 1947, Todd married Actress Joan Blondell. They were divorced on June 8, 1950, after Blondell filed for divorce on the grounds of mental cruelty.

In the 1950s Todd acquired the Harris and Selwyn Theaters in downtown Chicago. The Selwyn was renamed Michael Todd's Cinestage and made into a showcase for Todd-AO productions, while the Harris was renamed the Michael Todd Theatre and operated as a more conventional cinema. The facades of both theaters survive as part of the Goodman Theatre complex, although the interiors have been demolished.

In 1952, Todd made a production of the Johann Strauss II operetta A Night in Venice, complete with floating gondolas at the then-newly constructed Jones Beach Theatre in Long Island, New York. It ran for two seasons.

Before its release, Todd left the Cinerama Company to develop a widescreen process which would eliminate some of Cinerama's flaws. The result was the Todd-AO process, designed by the American Optical Company. The process was first used commercially for the successful film adaptation of Oklahoma! (1955). Todd soon produced the film for which he is best remembered, Michael Todd's Around the World in 80 Days, which debuted in cinemas on October 17, 1956. Costing $6 million to produce (equivalent to approximately $54,007,344), the movie earned $16 million at the box office. In 1957, Around the World in 80 Days won the Best Picture Academy Award.

Todd's third marriage was to the Actress Elizabeth Taylor, with whom he had a tempestuous relationship. The couple exchanged vows on February 2, 1957, in Mexico, and the ceremony was performed by the mayor of Acapulco. It was the third marriage for both the 24-year-old bride and her 47-year-old groom. Mario Moreno, better known as Cantinflas, was their witness. Todd and Taylor had a daughter, Elizabeth Frances (Liza) Todd, who was born on August 6, 1957.

On March 22, 1958, Todd's private plane the Liz crashed near Grants, New Mexico. The plane, a twin-engine Lockheed Lodestar, suffered engine failure, while being flown overloaded in icing conditions at an altitude that was too high for only one engine working under the heavy load. The plane went out of control and crashed, killing all four on board. Five days before the crash, Todd flew on this plane to Albuquerque to promote a showing of Michael Todd's Around the World in 80 Days. The city is located 78 miles east of the crash site.

A william Woolfolk novel from the early 1960s, entitled My Name Is Morgan, was considered to be loosely based on Todd's life and career.

In June 1977, Todd's remains were desecrated by graverobbers. The thieves broke into his casket looking for a $100,000 Diamond ring, which, according to rumor, Taylor had placed on her husband's finger prior to his burial. The bag containing Todd's remains was found under a tree near his burial plot. The bag and casket had been sealed in Albuquerque after Todd's remains were identified following the 1958 crash. Todd's remains were once more identified through dental records and were reburied in a secret location.