Ladd was drafted in the fourth round of the 1961 NFL Draft by the Chicago Bears. He was also taken by the American Football League’s San Diego Chargers with their 15th pick (119th overall) in the 1961 AFL draft. He chose to sign with the Chargers.

Ladd started wrestling in 1961. As a publicity stunt, some wrestlers in the San Diego area challenged Ladd to a private wrestling workout. Before long, Ladd was a part-time competitor in Los Angeles, during football’s off-season. Ladd became a huge draw in short order. When knee problems cut his football career short, Ladd turned to the more financially lucrative business of wrestling full-time in 1969. After a run as a fan favorite, Ladd became one of wrestling’s most hated heels during the 1970s, as well as one of the first black wrestlers to portray a heel character. He riled crowds with his arrogant and colorful demeanor during interviews, especially with his less than politically correct nicknames for opponents such as Wahoo McDaniel (whom he referred to as “the Drunken Indian”), and Mr. Wrestling (whom he called “the Masked Varmint” and insisted that he was an escaped criminal). Ladd also controversially employed a taped thumb, claiming the support was needed due to an old football injury. Often when Ladd appeared to be in serious trouble during a match he would walk out of the arena and accept a countout loss, known since as “pulling an Ernie Ladd”.

Ladd played in four AFL championship games, helping the Chargers win the American Football League title in 1963 with teammate Earl Faison, both members of the original Fearsome Foursome. Ladd, an American Football League All-Star from 1962 through 1965, was one of the AFL players that organized a walkout on the 1965 AFL All-Star Game due to the racism they experienced in New Orleans.

Ladd stated that he and teammate Earl Faison would play out their contract options, opting to take a 10 percent cut in salary in exchange for becoming free agents at the end of the season. A planned trade with the Oilers in early 1966 would have sent Faison and Ladd to Houston. However, both were declared free agents by AFL commissioner Joe Foss, who ruled that Oilers owner Bud Adams had tampered in trade dealings with the Chargers. Ladd refused to re-sign with the Chargers and suggested he might instead turn to professional wrestling full-time.

Eventually, Ladd signed with the Oilers and spent the 1966 season playing for them before moving in 1967 to the Kansas City Chiefs. There, with similarly king sized Grambling teammate and future NFL Hall of Famer Buck Buchanan (6’7″, 286 lbs), he filled out what was probably the biggest defensive tackle tandem in history. Both Ladd and Buchanan were inducted into the Grambling State University Athletic Hall of Fame.

After handily pinning Earl “Mr. Universe” Maynard the month prior, Ladd challenged Bruno Sammartino at Madison Square Garden for the WWWF title on March 1, 1976. In 1978, he wrestled WWWF champion Bob Backlund. When the International Wrestling Association had its brief run in the New York area, Ladd lost a two out of three falls match at Roosevelt Stadium, in Jersey City, New Jersey, to champion Mil Mascaras, two falls to one (he pinned Mascaras the first fall, was disqualified in the second, and was pinned by Mascaras in the third).

Boston Patriots center Jon Morris said Ladd was so big “It was dark. I couldn’t see the linebackers. I couldn’t see the goalposts. It was like being locked in a closet.” In 1981, he was inducted into the San Diego Chargers Hall of Fame.

Ladd retired from wrestling in 1986 due to recurring knee problems. He then returned to the WWF as a color commentator, calling the 20-man battle royal at Wrestlemania 2 (which featured NFL players) and then earning a trial run doing commentary for various shows, including the April 1986 show at Madison Square Garden. He was also used as a fill-in for matches on syndicated programming such as WWF Championship Wrestling. Ladd also teamed with Gorilla Monsoon and Johnny Valiant in the broadcast booth during The Big Event at C.N.E. Stadium in Toronto, Ontario. Ladd, Monsoon, and Valiant were the original three man team for the first few weeks of WWF Wrestling Challenge, before Ladd was replaced by Bobby Heenan and Valiant’s role was reduced significantly to only calling matches when Heenan had to be at ringside for one of the wrestlers he managed. Following this Ladd quietly left the WWF.

He was inducted into the WCW Hall of Fame in 1994 and the WWF Hall of Fame class of 1995, becoming the first (and for several years only) inductee in both halls.

Ladd also owned and operated Big Cat Ernie Ladd’s “Throwdown” BBQ Restaurant in New Orleans, Louisiana, until it was destroyed by Hurricane Katrina on August 29, 2005. In the disaster’s aftermath, he ministered to Katrina evacuees at the Astrodome. He was a friend of WWE Hall of Fame commentator Jim Ross.

Ladd was diagnosed with colon cancer in the winter of 2003–2004, being advised he had three to six months to live. Three years passed before he died on March 10, 2007 at the age of 68.