From 1998 to 2002, Varejão played for Franca Basquetebol Clube in the city of Franca, São Paulo. After averaging 17.7 points, 9.7 rebounds and 3 blocks per game in the first half of the 2001–02 season with them, he signed with FC Barcelona Bàsquet of the Liga ACB in January 2002. In nine EuroLeague games, he averaged 4.7 points, 4.0 rebounds, 2.0 assists and 1.1 blocks per game. In two regular season Liga ACB games, he averaged 4.0 points, 5.5 rebounds, 1.0 assists and 1.0 steals per game.

In 2002–03, Varejão appeared in four regular season Liga ACB games for Barcelona, averaging 8.2 points and 6.0 rebounds per game. While Varejão did not play in the 2003 Liga ACB playoffs, Barcelona, led by Juan Carlos Navarro, Šarūnas Jasikevičius and Dejan Bodiroga, won the Liga ACB championship. Varejão also played in 22 EuroLeague games (starting in one), helping Barcelona to their first ever EuroLeague championship. He averaged 4.1 points and 3.2 rebounds per game. He later scored one point in the EuroLeague championship game against Benetton Treviso.

Varejão has been a regular member of the senior Brazilian national team since 2001, winning a gold medal in 2003 at the Pan American Games and competing in every world cup between 2002 and 2019. On August 23, 2006, Varejão committed a controversial foul during a preliminary game of the 2006 FIBA World Championship against Greece, elbowing Greek point guard Nikos Zisis in the face.

Varejão was selected by the Orlando Magic in the second round of the 2004 NBA draft, 30th overall. On July 23, 2004, the Magic traded Varejão, along with Drew Gooden and Steven Hunter, to the Cleveland Cavaliers in exchange for Tony Battie and two future second-round picks.

In his rookie season, Varejão played in 54 games and averaged 4.9 points and 4.8 rebounds in 16 minutes played per game. He had a season high 14 points on March 26, 2005 against the Dallas Mavericks and a season high 14 rebounds on January 15, 2005 against the Utah Jazz. He ranked first in the NBA in steals per turnover (1.58), fourth in the NBA in offensive rebounds per 48 minutes (6.1), second among rookies in offensive rebounds per 48 minutes (6.1), and fourth in total rebounds per 48 minutes (14.3).

After missing the first 32 games of the 2005–06 season with a dislocated right shoulder, Varejão played in 48 games, starting four and averaging 4.8 points and 4.6 rebounds in under 16 minutes per game. Varejão had a season high 14 points on two occasions and a career high 18 rebounds on April 19, 2006 against the Atlanta Hawks.

On February 21, 2006, fans at Quicken Loans Arena attempted to break the Guinness World Record for “most people wearing wigs in a single venue” when 20,562 fans wore wigs given away before the game in celebration of Varejão’s unique hairstyle. All fans in attendance were instructed to put the wigs on during a timeout. It does not appear, however, that the fans were successful, as the Philadelphia Flyers now claim to have the wig wearing record with 9,315.

Varejão had a career high 17 points on December 11, 2006 against the New Orleans Hornets and a season high 17 rebounds (including a career high nine offensive rebounds) against the Utah Jazz on February 14.

In the 2007 offseason Varejão became a restricted free agent, and he did not sign a contract with the Cavaliers at the start of the 2007–08 NBA season. On December 4, 2007, he signed a two-year $11.1 million offer sheet (with a player option for a third year at $6.2 million) with the Charlotte Bobcats. Under the NBA’s collective bargaining rules, the Cavaliers had one week to match the offer sheet, which the Cavaliers did on December 5.

In 48 regular season games played (13 starts), Varejão averaged career highs in minutes (27.5), rebounds (8.3), offensive rebounds (2.8), and assists (1.1). He had a season high and tied his career high with 17 points on April 2, 2008 against the Charlotte Bobcats, a season high and career high tying 18 rebounds on January 11, 2008 (also against the Bobcats), and a career high six assists on March 8, 2008 against the Indiana Pacers. In his 13 starts, he averaged 7.9 points and 10.1 rebounds.

On November 7, 2008, Varejao scored a then career-high 18 points in a win against the Indiana Pacers. On January 2, 2009, Varejao eclipsed his personal best by scoring a career-high 26 points in a win over the Chicago Bulls. After the 2008–09 NBA season, Varejao reached an agreement with the Cavaliers to sign a six-year contract worth $42.5 million.

During the 2009–10 season, Varejão played in 76 games, but only started in seven. He still averaged 8.6 points per game and 7.6 rebounds per game in 28.5 minutes per game. On December 30, 2009, Varejão made the game-winning 3-pointer against the Atlanta Hawks. The Cavaliers once again made the playoffs in the 2009–10 season where they eventually lost to the Boston Celtics in the Eastern Conference Semifinals. To conclude the season, Varejão was also named to the NBA All-Defensive Second Team.

Once again, Varejão was Cleveland’s starting center, but this time he suffered a broken right wrist on February 10, causing him to miss the rest of the season. In 25 games played, Varejao averaged 10.8 points and 11.5 rebounds in 31 minutes per game. He set his then career high with 20 rebounds on January 31, 2012; he also added 20 points in the game.

On January 21, 2013, it was announced that Varejão would miss the remainder of the 2012–13 season after being hospitalized for a blood clot in his lung. He had been averaging 14.4 rebounds a game.

On October 31, 2014, Varejão signed a multi-year contract extension with the Cavaliers. Having returned to form in 2014–15 playing alongside LeBron James once again, Varejão tore his Achilles on December 23 against the Minnesota Timberwolves and was subsequently ruled out for the rest of the season. Without Varejão, the Cavaliers made it to the 2015 NBA Finals, but they lost to the Golden State Warriors in six games.

Varejão made his return to action in the Cavaliers’ season opening loss to the Chicago Bulls on October 27, 2015. In 11 minutes of action off the bench, he recorded two points and two rebounds.

On February 18, 2016, Varejão was traded, along with a future first-round draft pick, to the Portland Trail Blazers in exchange for a future second-round pick. Upon being acquired by Portland, he was waived by the team.

On February 22, 2016, Varejão signed with the Golden State Warriors. On February 24, he made his debut for the Warriors against the Miami Heat, recording one point, three rebounds and one assist in 10 minutes of action off the bench in a 118–112 win. The Warriors won an NBA record 73 games to eclipse the 72 wins set by the 1995–96 Chicago Bulls. Varejão played a small role for the Warriors to finish the 2015–16 regular season, averaging 2.6 points and 2.3 rebounds in 8.5 minutes off the bench in 22 games. The Warriors moved on to the 2016 NBA Finals after overcoming a 3–1 deficit in the Western Conference Finals against the Oklahoma City Thunder to win the series in seven games. In the NBA Finals, they faced Varejão’s former team, the Cleveland Cavaliers. According to the Elias Sports Bureau, Varejão became the first player in NBA history to play for both Finals teams in the same season. Despite the Warriors going up 3–1 in the series following a Game 4 win, they went on to lose the series in seven games to become the first team in NBA history to lose the championship series after being up 3–1.

On July 17, 2016, Varejão re-signed with the Warriors. On February 3, 2017, he was waived by the Warriors after averaging 1.3 points and 1.9 rebounds in 6.6 minutes over 14 games, with one start. The Warriors went on to win the NBA championship in 2017, and as a result, Varejão was offered a championship ring, which he accepted.

On January 17, 2018, Varejão signed with Flamengo. He played the second half of the 2017–18 season and then continued on with Flamengo for the 2018–19 season.