Ilgauskas made his professional debut in his birthplace of Kaunas, with local club Atletas in 1993. He averaged 20.3 points, 12.8 rebounds and 2.8 blocks per game in the 1994–95 season.

Ilgauskas made his debut with the Lithuania national team in 1994, when the team was qualifying for a spot in the EuroBasket 1995. He averaged 7.7 points and 7 rebounds per game. He later wanted to play for the Lithuania national team in the 2008 Summer Olympics, but the Cavaliers did not permit him to play due to his injury history.

Ilgauskas was selected by the Cleveland Cavaliers with the 20th overall pick in the 1996 NBA draft. On August 1, 1996, he signed a multi-year deal with the Cavaliers. In the earliest parts of his career he suffered through a myriad of foot and ankle injuries. He spent the entire 1996–97 season on the injured list due to a broken bone in his right foot.

He was named the most valuable player of the Rookie Challenge during All-Star Weekend and selected to the All-Rookie First Team in 1997–98. He signed a contract extension in 1998 that was worth $70.9 million over 6 years. However, Ilgauskas played in only 5 games over the next two seasons. On January 26, 2000, he had a surgery on a fractured navicular bone in his left foot.

He re-gained the starting center spot for the Cavaliers in 2000–01. He was injured again in December 2000 and was out for the season. The injury dealt a blow to the Cavaliers. After winning 15 out of 23 games with Ilgauskas, they finished with a 30–52 record.

He returned in December 2001 and was mostly used as a backup to Chris Mihm for the rest of the season.

The Cavaliers drafted high school phenomenon and future NBA MVP LeBron James in 2003. James teamed up with Ilgauskas and Drew Gooden to form the core of the team. Ilgauskas only missed 9 games over the next three seasons and was selected as an All-Star again in 2005.

On July 12, 2005, Ilgauskas signed a contract extension with the Cavaliers. The deal was reportedly worth over $55 million over 5 years.

For the next four seasons, Ilgauskas was the starting center for the team, which had turned into a contender. They reached the NBA Finals in 2007 and the Eastern Conference Finals in 2009. In summer 2009, the Cavaliers acquired Shaquille O’Neal. When asked about the trade, Ilgauskas responded: “I was just reading the news. That means I’ll probably be coming off the bench.” On December 2, 2009, Ilgauskas came off the bench in a game against Phoenix Suns to break the team record for career games played, overtaking General Manager Danny Ferry.

Ilgauskas married his wife, Jennifer, during the summer of 2004. In 2007, the couple lost a set of twins due to pregnancy complications that caused the infants to be born four months premature. In the summer of 2009, Ilgauskas adopted two Lithuanian brothers (aged five and four at the time) from his hometown of Kaunas.

During a press conference in 2008 he said: “I would like to thank to everyone, especially federation, all the insurers for all their efforts and determination. They have been working in days and in nights so that my dream – to play for the national team in the Olympics would come true… It’s a pity that I was unable to do that previously… I think everyone of us aren’t friends with Cleveland currently, but that is the way we had to go and we did… During the season I got elbowed into my back… After the season I rested a few weeks and began training because I wished to arrive the training camp from the beginning and to prepare, however the pain returned… Doctors told that there are two moves: resting or operation after which you have to rest for two months… I really wished to play a lot and it would hurt in my heart if I would have to sit and would be unable to play. If I did not want that, I wouldn’t have gone through all these roads of the cross… Of course, the club and the NBA didn’t helped, were throwing sticks into the wheels… It’s a business for them. The life doesn’t end with this”.

On February 17, 2010, Ilgauskas, along with a 2010 first round pick and the rights to Emir Preldžič, was traded from the Cavaliers to the Washington Wizards as part of a three-team, six-player trade that sent Antawn Jamison from Washington to Cleveland, Al Thornton from the Los Angeles Clippers to Washington, Drew Gooden from Washington to Los Angeles, and Sebastian Telfair from Los Angeles to Cleveland. On February 25, 2010, the Wizards bought out his contract, making him a free agent. Ilgauskas did not play in any games for the Wizards. It was possible for Ilgauskas to return to the Cavaliers, but only after a 30-day waiting period policy required for players traded from their former teams after being bought out of their contract by their new team. He was still free to sign with any other team.

On March 23, 2010 Ilgauskas signed a one-year deal for the remainder of the 2009–10 season with the Cleveland Cavaliers. He made his return a day later in a win over the New Orleans Hornets. In his first home game back with the team, against the Sacramento Kings, Ilgauskas received huge ovations and support from the crowd. Quicken Loans Arena was affectionately renamed “The Z” for the day, in honor of the Lithuanian.

The 2010 NBA Playoffs marked the first time in Ilgauskas’ career in which he was not a significant part of the Cavaliers’ rotation. Ilgauskas saw only 69 minutes of floor time in the entire postseason, resulting in averages of 1.7 PPG and 1.6 RPG, far below his career playoff production. The Cavaliers were eliminated by the Boston Celtics in the Eastern Conference semifinals.

On July 17, 2010, Ilgauskas signed with the Miami Heat. The Heat’s signings of Chris Bosh, Dwyane Wade and long-time teammate LeBron James influenced Ilgauskas’ decision to join the Heat. On December 2, 2010, during the Heat’s first game in Cleveland, the fans cheered Ilgauskas in pre-game introductions, while booing the rest of the starters, including James. The Heat made it to the 2011 NBA Finals, but fell short to the Dallas Mavericks in six games.

In September 2011, Ilgauskas announced that he was retiring from basketball, saying he wanted to spend more time with his family as well as citing long-term personal physical fatigue and basic bodily wear-and-tear.

On January 11, 2012, Ilgauskas made a return to Cleveland when he was hired by then Cleveland Cavaliers GM Chris Grant to serve as his assistant. His duties included evaluating amateur and pro talent prospects.

Ilgauskas became a United States citizen in 2013. Due to that, he lost his Lithuanian citizenship, as the country limits the possibility of dual citizenship.

On March 8, 2014, Ilgauskas’ number 11 was retired by the Cleveland Cavaliers, making him just the third European to be honored in this way by an NBA team, after Dražen Petrović and Vlade Divac.

On September 18, 2015, Ilgauskas joined Saint Ignatius High School as the assistant coach for the boys’ team.