Ferrigno was born in Brooklyn, New York to Matthew Ferrigno,an Italian American New York City Police Department Lieutenant, and his mother Victoria. As an infant, he suffered an ear infection and lost some of his hearing. Ferrigno started weight training at age 13, citing body builder and Hercules star Steve Reeves as one of his role models.

After graduating from Brooklyn Technical High School in 1969, Ferrigno won his first major titles, IFBB Mr. America and IFBB Mr. Universe, four years later. In 1974, he came in second on his first attempt at the Mr. Olympia competition. He then came third the following year, and his attempt to beat Arnold Schwarzenegger was the subject of the 1975 documentary Pumping Iron. Following this, Ferrigno left the competition circuit for many years, a period that included a stint as a defensive lineman for the Toronto Argonauts in the Canadian Football League.[citation needed]

Ferrigno competed in the first World's Strongest Man contest in 1977, where he finished fourth in a field of eight competitors. While competing, Ferrigno regularly went to see a physician who checked up on whether he was doing damage to his body.

Ferrigno signed up with Universal Studios in 1977, and beat out both Arnold Schwarzenegger (although both Ferrigno and Schwarzenegger himself have gone on record saying Arnold was not in the running[citation needed]) and Richard Kiel for the title role opposite Bill Bixby as the Hulk in The Incredible Hulk. Richard Kiel was hired for the series first, and scenes were filmed. It was quickly determined he was not muscular enough, and Ferrigno was signed. One quick shot of Kiel remains in the pilot movie. Although he did not share a line with Bixby on the set (except for one episode, "King of the Beach"), the two were friends. Ferrigno continued playing the Hulk role until 1981, although the last two episodes were not broadcast until May 1982. Later, he and Bixby co-starred in three The Incredible Hulk TV movies. There were major talks of another movie, The Rebirth of The Incredible Hulk, but due to Bixby's death, the project never went beyond the earliest stages of development. Ferrigno continued to keep in touch with Bixby until his death on November 21, 1993. Ferrigno attended Bixby's funeral in California. Early in his career he lived in Columbus and trained with Arnold Schwarzenegger.

During competition, Lou Ferrigno weighed 285 lb (130 kg) in 1975, and 316 lb (143 kg) in 1992; at 6 ft 5 in (1.96 m) he was one of the tallest professional bodybuilders at that time. He currently stands 6 ft 3½ in (1.92 m).

In the early 1990s, Ferrigno returned to bodybuilding, competing for the 1992 and 1993 Mr. Olympia titles. Finishing 12th and 10th, respectively, he then turned to the Masters Olympia, coming second in 1994 to Robby Robinson. After this, he retired from competition.

He made a cameo in the 2003 film Hulk as a security guard and was in one deleted scene. He has also done guest appearances and advertisements, including one for LongHorn Steakhouse.

He again appeared as a security guard in 2008's feature film The Incredible Hulk as well as voicing the Hulk. Furthermore, Ferrigno has been the favorite choice to play the voice of the Hulk in several animated adaptations as well as in the most recent film after being publicly offered at the 2008 New York Comic Con by The Incredible Hulk director Louis Leterrier.

Ferrigno appeared as himself in the 2009 comedy I Love You, Man.

Carla Ferrigno told Reuters that her husband had been helping Michael Jackson train in advance of his 2009-2010 concerts at the time of his death. Jackson and Ferrigno have worked together in the past.