First-year head coach, Randy Ayers, earned his first career win, as the Philadelphia 76ers defeated the heat in the season opener against Miami. After dropping the first two road games of the year, Glenn Robinson made his Philadelphia 76ers debut and helped the team earn its first road win of the year over Portland. However, a left ankle sprain would sideline Robinson for the next month. Allen Iverson earned Easter Conference Player of the Week honors for the week ending on Nov. 16, helping the Philadelphia 76ers post a 2-1 record that included a 36-point, 12-assist performance in a win over defending champion San Antonio Spurs. The Philadelphia 76ers dropped four of their next six games, but bounced back with a victory over the Detroit Pistons in Larry Brown’s first return to Philadelphia. Iverson finished November with his sixth career 50-point performance against Atlanta, as the Philadelphia 76ers evened their record at 9-9.

After losing the first two games of the New Year, Iverson's return sparked wins in three out of the next four games, improving the Philadelphia 76ers' season record to 18-20. On Jan. 14, the Philadelphia 76ers erased a 15-point forth quarter deficit at Dallas to force overtime, but the Mavericks held on and won in double-overtime. In the losing effort, two Philadelphia 76ers players - Robinson and Iverson - scored 30 points or more for the first time since April 1, 1998. Additionally, center Samuel Dalembert recorded a career-high with 24 points, adding 16 rebounds and four blocks. After dropping seven of their next eight games, Philadelphia fell to 19-27 on the year, marking the first time in which the Philadelphia 76ers had been eight games under .500 since the end of the 1997-98 season. The struggles continued, as Iverson's career-best streak of 51-consectutive games with at least one steal came to an end in the Philadelphia 76ers' loss to Memphis on Jan. 17. On Jan. 23, in a loss to Orlando, Iverson became the 10th-fastest player in NBA history to reach the 14,000-career point plateau.

The Philadelphia 76ers dropped four of the first five games in February. However, in a win over the Lakers, Robinson became the 12th active player with 14,000 career points. On Feb. 10, 76ers President and General Manager, Billy King, announced that Chris Ford would serve as Interim Head Coach for the remainder of the season. In Ford's first game, the Philadelphia 76ers easily defeated Washington 113-88 and entered the All-Star break with a 22-31 record.

The Philadelphia 76ers, who lost their final four games of the season, were officially eliminated from playoff contention following a loss at New Jersey on April 11. The Sixers closed out the season with a loss at Orlando, completing the season with a 33-49 record. Dalembert ended the season on a streak of 17-straight games with at least one blocked shot and completed the season with 189 blocks, which ranked him sixth in total blocks in the NBA and seventh on the Philadelphia 76ers all-time single-season record books. Ford guided the Sixers to a 12-18 record, as injuries took a toll on the Sixers lineup. Philadelphia was forced to use 25 different starting lineups and Sixers' players missed a league-high 350 games