Jefferson's 2005–06 season was widely considered a disappointment, mostly due to a series of ankle injuries and a torn meniscus in his right knee which limited him to playing in 59 games.

After experiencing lingering pain after participating in the Las Vegas Summer League, a CAT scan revealed bone spurs.

In what some considered a breakout performance against the New Jersey Nets on December 9, 2006, he scored a career-high 29 points and grabbed 14 rebounds,[5] which tied a career high (set on May 5, 2005, in a playoff game against the Indiana Pacers).

[7] On July 31, 2007, Jefferson was traded, along with Gerald Green, Ryan Gomes, Theo Ratliff, Sebastian Telfair and draft picks, to the Minnesota Timberwolves in exchange for Kevin Garnett.

Jefferson also defined himself as one of the premier big men in the NBA by being only one of four players to average 20 points and 10 rebounds (the others being Dwight Howard, Carlos Boozer and Antawn Jamison).

Jefferson claimed that he felt a pop in his knee and the injury resulted in a complete tear to the ACL which required reconstructive surgery that ended his season.

His first season in Utah brought numerous ups and downs, including the in-season departures of Williams and coach Jerry Sloan.

[20] In the lockout shortened 2011–12 season, Jefferson furthered his improvement, transitioning into his role as team leader while continuing to put up impressive numbers.

Behind Jefferson's strong season, the young Jazz finished 36–30 and secured the eighth seed in the West where they faced the San Antonio Spurs in the first round.

While Jefferson did his best to contain Spurs' superstar Tim Duncan, Utah simply couldn't measure up against San Antonio.

He posted a career-high 40 points late in the season against the Minnesota Timberwolves and was poised to be the catalyst for the Jazz to make a return trip to the playoffs.

Despite the season ending early, Jefferson again established himself as a force down low and figured to be one of the most valued free agents heading into the offseason.

Though he was slowed by the ankle injury, upon his return, Jefferson showed glimpses of promise while working himself back into rhythm as by the time January rolled around, he was finally healthy and ready to dominate.

He continued his high level of play en route to winning the Eastern Conference Player of the Month for his performance in March 2014.

[25] After kicking back into form in 2013–14 with his best averages since 2008–09, Jefferson continued to thrive with the young, newly named Charlotte Hornets in 2014–15.

On November 7, 2014, Jefferson scored a season-high 34 points in the Hornets' 122–119 double overtime win over the Atlanta Hawks to move to a record of 3–3.

[29] His recurring groin injury flared up again on December 29 against the Milwaukee Bucks as he left the game during the fourth quarter and did not return after managing just 6 points and 8 rebounds.

[32] After missing nine games with the injury, Jefferson returned on January 19, recording 8 points and 5 rebounds in a Hornets win over the Minnesota Timberwolves.

[33] He came off the bench for a further three games before reclaiming his starting spot on January 28 against San Antonio and subsequently recorded 17 points and 16 rebounds in a loss to the Spurs.

[34] On March 11, in a loss to the Sacramento Kings, Jefferson left the game late in the third quarter due to a strained right calf after managing 9 points and 6 rebounds in 24 minutes of action.

[45] In the team's regular season finale on April 13, Jefferson scored 26 points off the bench in a 117–103 win over the Orlando Magic, helping the Hornets finish as the sixth seed in the Eastern Conference with a 48–34 record.

[46] In Game 2 of the Hornets' first round playoff series match-up with the Miami Heat, Jefferson scored 16 second-quarter points to finish with 25 on 12-of-17 shooting off the bench in a 115–103 loss.

[48][49] He made his debut for the Pacers in their season opener on October 26, 2016, recording seven points and six rebounds off the bench in a 130–121 overtime win over the Dallas Mavericks.