After graduating from high school in 1969, Ferrigno won his first major title, IFBB Mr. America. Four years later, he won the title IFBB Mr. Universe. Early in his career he lived in Columbus, Ohio and trained with Arnold Schwarzenegger. In 1974, he came in second on his first attempt at the Mr. Olympia competition. He came in third the following year, and his attempt to beat Arnold Schwarzenegger was the subject of the 1975 documentary Pumping Iron. The documentary made Ferrigno famous.

During competition, Ferrigno at 6 ft 5 in (1.96 m) weighed 268 lb (130 kg) in 1975, and 315 lb (142 kg) in 1992.

In 1977, Ferrigno was cast as the Hulk in The Incredible Hulk. Ferrigno and Bill Bixby – who played the Hulk's "normal" alter ego – became friends; Ferrigno has described Bixby as a "mentor" and "father figure" who took him under his wing. Ferrigno also singles out the instances in which Bixby directed Ferrigno in some episodes as particularly memorable. 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.

In November 1978 and again in May 1979 Ferrigno appeared in Battle of the Network Stars.

Ferrigno married Susan Groff in 1978, divorcing a year later. On May 3, 1980, he married psychotherapist Carla Green, who then also began serving as his manager; she later became a personal trainer. They have three children, Shanna, born 1981; Louis, Jr., born 1984; and Brent, born 1990. Shanna has a recurring role as Nurse Janice in Days of Our Lives, and appeared in the NBC series Windfall, as well as the television movie Within, and in 2005 she appeared in the E! reality television series, Filthy Rich: Cattle Drive. Louis, Jr. was a linebacker for the University of Southern California Trojans football team.

In 1983, Ferrigno appeared as John Six on the short-lived medical drama Trauma Center.

Ferrigno trained Michael Jackson on and off beginning in the early 1990s, and in 2009, he helped Jackson get into shape for a planned series of concerts in London, which were ultimately cancelled due to Jackson's untimely death.

Ferrigno played himself during intermittent guest appearances on the CBS sitcom, The King of Queens, beginning in 2000 and continuing until the program's conclusion in 2007. He and his wife Carla were depicted as the main characters' next-door neighbors. Because of his role as the title character on The Incredible Hulk, he is often the target of Hulk jokes by Doug and his friends.

He made cameo appearances as a security guard in both the 2003 film Hulk and the 2008 film The Incredible Hulk, in which he also voiced the Hulk.

In February 2006, Ferrigno was sworn in as a Los Angeles County, California, reserve sheriff's deputy, Level II.

Ferrigno has his own line of fitness equipment called Ferrigno Fitness. In January 2009, he provided equipment to The Price Is Right for use as a One Bid prize, and demonstrated the equipment himself.

In November 2010, Ferrigno was sworn in as a member of a Maricopa County, Arizona, volunteer sheriff posse, which also includes actors Steven Seagal and Peter Lupus, in order to help control illegal immigration in the Phoenix Valley area.

In June 2012, Ferrigno was sworn in as a reserve deputy to the San Luis Obispo County, California, Sheriff's Department. There he completed his level I law enforcement academy, bringing his training up to full peace officer status.

In September 2013, Ferrigno was sworn in as a special deputy to the Delaware County, Ohio, Sheriff's Department.

In 2014, Ferrigno appeared as Zaminhon, the Orion slave trader, in the Star Trek Continues episode "Lolani".

In 2016, Ferrigno appeared as a playable Lego version of himself in Lego Marvel's Avengers.

Due to ear infections suffered soon after birth, Ferrigno lost 75 to 80% of his hearing and has been using hearing aids since the age of five. Ferrigno says his hearing loss helped shape his sense of determination in his youth, saying, "I think that if I wasn't hard of hearing I wouldn't be where I am now. Early on, as a youngster it was difficult, but I’m not ashamed to talk about it because many people have misconceptions about hearing loss; like who has hearing loss and what it’s like not to hear, so I do talk about it. I think my hearing loss helped create a determination within me to be all that I can be, and gave me a certain strength of character too. Anytime I do a movie or a TV show, I make them aware of my hearing loss at the beginning, and that makes it much easier for all of us to communicate and get the job done."