The New Orleans Saints selected Anzalone in the third round (76th overall) of the 2017 NFL Draft.[7] He was the tenth linebacker selected in 2017.[8] On June 2, 2017, the Saints signed Anzalone to a four-year, $3.46 million contract that included a signing bonus of $864,592.[9]
Anzalone earned a starting outside linebacker job for the Saints as a rookie, starting all four games in which he played. In Week 4 against the Dolphins, he suffered a shoulder injury and was placed on injured reserve on October 4, 2017.[10]
After playing in all 16 games in the 2018 season, Anzalone was placed on injured reserve on September 16, 2019.[11]
Detroit Lions
Anzalone signed with the Detroit Lions on March 24, 2021.[12] He entered the 2021 season as a starting linebacker. He started the first 14 games before suffering a shoulder injury in Week 15. He was placed on injured reserve on December 20.[13]
In March 2022, Anzalone re-signed with the Lions.[14]
On March 13, 2023, Anzalone signed a three-year, $18.75 million contract extension with the Lions.[15]
In his third season with the Lions, Anzalone was selected as a 2024 NFL Pro Bowl Alternate.