In Fort Lauderdale, Huizenga started a garbage hauling Business, as his grandfather had done in Chicago in 1894. In 1962, he started the Southern Sanitation Service by borrowing US$5,000 from his Father and sweet-talking with a rival trash hauler into selling him used trucks. Beginning with a single garbage truck in 1968, and pursuing customers in an aggressive manner, he created Waste Management, Inc., an entity that would eventually become a Fortune 500 company. Huizenga purchased many independent garbage hauling companies; by the time he took the company public in 1972, he had completed the acquisition of 133 small-time haulers. In the early 1980s, he had grown Waste Management into one of the largest waste-disposal companies in the United States. In 1984, he left the company and soon again, he was buying companies including suppliers of portable toilets and water bottles for home coolers.

Huizenga was born at Little Company of Mary Hospital, in Evergreen Park, Illinois, on December 29, 1937, as the first child into a family of garbage haulers. He had one sister, Bonnie, who was five years younger than him. He attended Timothy Christian School until his mid-teens. In early 1953, the Huizenga family moved to Florida and settled in the Fort Lauderdale area, where his Father began working as a building contractor in order to take advantage of the real estate boom there.

The remainder of Huizenga's high school years were spent at Pine Crest School, where he was a member of the football team and senior class treasurer. After high school graduation in 1956, he moved back to Chicago where most of his friends, grandparents and other relatives still lived, and enrolled for three semesters at Calvin College, a liberal arts college in Grand Rapids, Michigan, but he dropped out before the end of his sophomore year. For approximately five years after graduation, he was taking on low-wage jobs and enrolled briefly for six months in September 1959 in the army reserves on full time Service.

On September 10, 1960, he married Joyce Vander Wagen, a woman with a Dutch background, whom he met while in high school. He had known Joyce since his early school years in Evergreen Park. Wayne and Joyce had two children, Wayne Jr. and Scott. The marriage ended in divorce in 1966. Huizenga married his second wife, Martha Jean "Marti" (née Pike) Goldsby, a native of San Antonio, Florida, in April 1972. She was a secretary, who had done billing and clerical work in one of his businesses. He later adopted her son, Robert Ray and daughter Pamela. The couple remained married until her death on January 3, 2017, following a fourteen-year battle with cancer.

In the 1980s, he began acquiring some 2,000 acres about 30 miles north of West Palm Beach. In 1996, he based the Floridian Golf & Yacht Club there, an exclusive golf club "with enough estate homes on the property to cover his costs," whose course was designed by Gary Player, where he extended free privileges to some two hundred "friends, relatives, and Business associates," including actors Michael Douglas and Catherine Zeta-Jones and retired GE Chairman Jack Welch. He renamed his yacht Floridian, before selling, in 2010, the Floridian club and estate to Texas Entrepreneur Jim Crane.

Huizenga repeated the process with Blockbuster Video, acquiring a handful of stores in 1987, with the company becoming the leading movie-rental chain in the U.S. by 1994. After a process of building and acquiring auto dealerships, in 1996, he formed AutoNation, which became the nation's largest Automotive dealer.

In the early 1990s, Huizenga served a two-year probationary period with the National Football League as an owner, with the stipulation that he not buy another team.

In 1992, Huizenga was named a "Distinguished American" by the Horatio Alger Association in 1992 for his funding of scholarships throughout Florida. He was named its 2008 Norman Vincent Peale Award recipient. His donations help fund the association's annual National Scholar awards.

In 1994, Huizenga's brother-in-law attempted to purchase the NBA's Miami Heat, but was unsuccessful.

Huizenga operated the Florida Panthers as a public holding company, buying numerous real estate properties in the name of his Panthers Holding Group. Capitalizing on the team's 1996 drive to the Stanley Cup finals, he sold shares to the public, whose enthusiasm for the club drove civic Leaders in Broward County to use public money to build a new arena for the team. Huizenga used the hockey team's stock as currency to begin building yet another Diversified enterprise, buying two resort hotels owned partly by Huizenga and other Panthers officials. His original investment in the Panthers had nearly tripled in total value to $150 million.

When he sold the Marlins, Huizenga, who still owned the Pro Player Stadium, retained the rights to skybox tickets and club seat customers, as well as 62.5% of parking revenue, and 30% of concessions. Economist Andrew Zimbalist commented that "Huizenga made a killing when he sold the team for $150 million [in 1998] and had the lease for this stadium that enabled him to keep just about all the stadium revenue."

In 2001, he sold the Panthers to pharmaceutical businessman and friend Alan Cohen and Cohen's partner, former NFL quarterback Bernie Kosar, for approximately $100 million. In December 2017, 25 years after he created the club, the Panthers retired the no. 37 shirt in honor of Huizenga. His family chose the number because it was his "birth year and lucky number."

In 2004, Huizenga purchased a private luxury yacht from the Australian professional Golfer Greg Norman. The yacht cost $77 million and was further modified by Huizenga to feature a helipad for a 12-seat helicopter. In August 2004, Power & Motoryacht ranked it as the 43rd-longest yacht in the world.

In 2008, Huizenga sold 50% of the team and 50% of the stadium to Stephen M. Ross, chairman of The Related Companies. Huizenga remained the managing general partner of the franchise until January 2009, when he sold another 45% of the team and as much of the stadium to Ross. Thus, Ross became managing general partner with 95% ownership of the Dolphins and the stadium, and Huizenga retained a 5% share of both club and stadium. Huizenga remained the proprietor of 50% of the land.

In 2010, Huizenga along with Steve Berrard, former CEO of Blockbuster Video and AutoNation, took on a majority stake in Swisher Hygiene, after paying $8.1 million to founder Patrick Swisher and his wife, Laura. Swisher Hygiene went on to be traded on the NASDAQ and the Toronto Stock Exchange via a 2010 reverse takeover deal in which the company acquired the publicly traded CoolBrands International, a Canada-based frozen food and dessert manufacturer. CoolBrands had divested its core businesses in 2007, leaving little more than a corporate shell.

In 2012, the City of Fort Lauderdale, Florida, renamed Southeast 9th Street in the Rio Vista neighborhood Wayne Huizenga Blvd.

Huizenga died of cancer at his home in Fort Lauderdale, Florida, on the night of March 22, 2018. He was 80.