Fertitta was a partner in the first Landry’s Restaurant, Landry’s Seafood, which opened its doors in the Houston suburb of Katy, Texas, in 1980. A year later, he helped open Willie G’s Seafood & Steaks, a more upscale restaurant in Uptown Houston.

In 1986, Fertitta gained controlling interests of both locations, and in 1988, became sole owner of Landry’s Restaurants. In 1993, he took Landry’s, Inc. public and the company grew quickly, adding concept after concept.

In addition to restaurants, hotels, and casinos, Landry’s also owns amusement parks, aquariums, and the Kemah Boardwalk. Landry’s, Inc. first acquired the Kemah Boardwalk in 1999. After acquiring the boardwalk, Fertitta added a few Landry’s restaurants, and a few rides. In 2007, he added the Boardwalk Bullet which is a high speed wooden roller coaster. He also added the Boardwalk Fanta Sea, which is a luxury yacht cruise service where guests ride along the Galveston Bay.

In 2000, Landry’s acquired the land on the 400 block of Bagby in Downtown Houston. The deal came from a proposal of the City of Houston to redevelop the fire station. After redeveloping the building, the aquarium added the shark tank and restaurant before opening in 2003.

In 2003, Fertitta bought the naming rights to the Crawford Boxes seating section of Minute Maid Park, calling it “Landry’s Crawford Boxes”. The term has become a commercial moniker during radio and television broadcasts. A Landry’s sign is placed above the section, along with many of the company’s subsidiaries. Traditionally, when a fan catches a home run, they are awarded a gift certificate to one of Landry’s restaurants. Landry’s promoters often visit the section and give away items such as T-shirts.

In 2004, Fertitta was elected to the Texas Business Hall of Fame, becoming the second-youngest Texan to ever earn that distinction, behind only Michael Dell.

Fertitta first built the Key Largo Hotel in Galveston, Texas to buy the rights to Landry’s. After acquiring restaurants under the company, Fertitta started focusing more on the hospitality division of Landry’s and acquired the San Luis Resort, Spa, & Conference Center in Galveston, Texas. He also partnered with the City of Galveston to build the conference center in 2004 inside the resort. Fertitta since acquired two additional hotels on the island, including the Holiday Inn On the Beach in 2003, and the Hilton Galveston Island Resort in 2004, which stands adjacent to his San Luis Resort. In 2015, Fertitta added the Villas at San Luis section of the hotel, which consists of ultra-luxury villas with direct access to both the beach and the hotel’s pool.

Landry’s first expanded to casinos in 2005 when it bought Golden Nugget Casinos, including locations in Las Vegas and Laughlin, Nevada. Since then, Landry’s has opened casinos in Atlantic City, New Jersey; Biloxi, Mississippi; and Lake Charles, Louisiana. The Golden Nugget Atlantic City was previously called the Trump Marina. Fertitta purchased this casino from Trump Entertainment Resorts in 2011.

In 2008, Fertitta was named chairperson of the Houston Police Department’s Police Foundation, supplying gear and equipment for Houston Police Officers. He serves on the Executive Committee for the Houston Livestock Show and Rodeo.

In 2009, Texas Governor Rick Perry appointed Fertitta to the Board of Regents of the University of Houston System.

In 2010, Fertitta, who already owned the majority of Landry’s, Inc. stock, purchased all outstanding shares, becoming sole owner again. In 1993, the company was valued at approximately $30 million.

By 2011, the company’s value had skyrocketed to a value of more than $1.7 billion. As of 2013, the company, under the leadership of Fertitta, owns and operates more than 500 restaurant/entertainment/gaming/hospitality locations. In total, Landry’s, Inc. employs more than 50,000 people and controls $3.2 billion in assets.

Fertitta redeveloped the pleasure pier in Galveston, Texas, after the pier had closed after damages by Hurricane Ike. The pier reopened in 2012 as the Galveston Island Historic Pleasure Pier. The redeveloped pier includes an amusement park, Bubba Gump Shrimp Company restaurant, as well as shops.

On January 12, 2016, it was announced that Fertitta would star in his own reality TV show titled Billion Dollar Buyer on CNBC. Billion Dollar Buyer premiered on March 22, 2016 at 10 P.M. Eastern Time. After receiving success during the first season, a second season was announced, featuring over twice as many episodes.

He is the third cousin of former UFC owners Lorenzo and Frank Fertitta. An avid sports fan, Fertitta is a vocal supporter of the University of Houston Cougars and can be seen at most Cougar football and basketball games as well as court side for Houston Rockets basketball games. In 2016, Fertitta donated $20 million to rebuild the University of Houston’s basketball home of Hofheinz Pavilion, since renamed Fertitta Center, along with donations for the construction of TDECU Stadium.

His portfolio includes: The Golden Nugget Hotel and Casinos; Morton’s The Steakhouse; Rainforest Cafe; Bubba Gump Shrimp Co.; McCormick & Schmick’s Seafood & Steaks; Saltgrass Steak House; Claim Jumper; Chart House; The Oceanaire; Mastro’s Restaurants; Grotto Restaurants, The Boathouse Restaurants and Vic & Anthony’s Steakhouse. In 2017 he acquired half of EMM group, owner of the Catch Restaurants.

On September 4, 2017, he agreed to purchase the Rockets from Leslie Alexander, pending league approval, for an NBA record $2.2 billion. On October 6, 2017 Fertitta was approved by the NBA to own the Houston Rockets. Fertitta paid for the Rockets by selling $1.415 billion worth of bonds and was competing with Houston-native singer Beyonce Knowles to purchase the team. By buying the Houston Rockets he also became the owner of Clutch Gaming, a professional eSports organisation focused on League of Legends.

On May 16, 2018, Fertitta announced that Landcadia would acquire Waitr.

On September 17, 2019, Fertitta released a book, Shut Up and Listen! Hard Business Truths That Will Help You Succeed, in which he details his journey to success and offers advice to other entrepreneurs on their business ventures. Each chapter contains “Tilmanism’s” which focus on 6 important rules for any entrepreneur to follow: “(1) Be the Bull, (2) No Spare Customers, (3) Change, change, change, (4) Know Your Numbers, (5) Follow the 95/5 Rule, and (6) Take No Out of Your Vocabulary”

On October 4, 2019, the Houston Rockets general manager Daryl Morey issued a tweet that supported the 2019–20 Hong Kong protests which drew criticism from Fertitta who said that while Morey was the best general manager in the NBA, the Rockets were not a political organization. Morey later deleted the tweet.

In April 2020, Governor Greg Abbott named Fertitta to the Strike Force to Open Texas – a group “tasked with finding safe and effective ways to slowly reopen the state” during the COVID-19 pandemic.