Poul Hubertz's 13th goal of the season earned Northampton a win which secured a ninth-placed finish in League One.
Adebayo Akinfenwa put the home side ahead from close range after Tranmere failed to clear Daniel Jones' cross.
They had chances to increase their lead but Tranmere levelled through Chris Greenacre's overhead kick.
Substitute Hubertz grabbed the winner, heading home a Jones free-kick, while Tranmere's Ian Goodison was sent off on 80 minutes for a second booking.
Northampton: Dunn, Crowe, Gyepes, Doig, Jones, Gilligan, Coke (Hubertz 54), Dolman, Dyer (Holt 65), Larkin (Jackman 65), Akinfenwa. Subs Not Used: Burnell, Taylor.
Booked: Jones, Hubertz, Gilligan.
Goals: Akinfenwa 3, Hubertz 68.
Tranmere: Coyne, Stockdale (Jennings 58), Goodison, Chorley, Taylor, Shuker (Davies 67), McLaren, Kay, Sherriff (Curran 79), Moore, Greenacre. Subs Not Used: Achterberg, Mullin.
Sent Off: Goodison (80).
Booked: Goodison.
Goals: Greenacre 43.
Att: 5,088
Ref: Gavin Ward (Surrey).
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