On September 11, 2016, Fitzgerald had eight receptions for 81 yards and two touchdowns, while becoming the 10th player to reach 100 career touchdowns, in the season-opening 23–21 loss to the New England Patriots on "NBC Sunday Night Football". In the fifth game of the season, he had six receptions for 81 yards and two touchdowns in the 33–21 loss to the San Francisco 49ers. On November 13, he had 12 receptions for 132 yards in another strong outing against the 49ers in a 23–20 victory. In the regular season finale, 44–6 victory over the Los Angeles Rams, he had five receptions for 43 yards and scored his first receiving touchdown since the first meeting with the 49ers. The Cardinals finished with a 7–8–1 record and missed the playoffs.