In three seasons with the Saints, he started all 51 games he played in and posted 228 tackles (161 solo), one sack, ten interceptions for 195 yards in returns, including one brought back for a touchdown, 24 pass breakups, three forced fumbles and two fumble recoveries. In 2022, Mathieu led the Saints with three interceptions and tied for the team lead in picks in both 2023 (four) and 2024 (three). In 2024, Mathieu was the only member of the secondary to start all 17 games and finished with 62 tackles (47 solo), three interceptions, seven pass breakups, two forced fumbles and one fumble recovery to lead the team with four takeaways.

Immensely respected off the field, Mathieu was selected a team nominee for the NFL Walter Payton Man of the Year both as a member of the Saints (2023) and Chiefs (2021). Through his Tyrann Mathieu Foundation, Mathieu worked to create positive change in the lives of youth and families in need, particularly those in his hometown; by providing resources and experiences, especially in the summer and around the holidays.