The impressive Stephen Ireland gave City a deserved lead in the 18th minute by lashing home a Bradley Wright-Phillips cross.
Fowler, who is recovering from a back injury, then showed his class three minutes later by lifting the ball over the Wigan keeper from Antoine Sibierski's through-ball.
The Wigan keeper saved from Fowler and Lee Croft, who also caught the eye, as City continued to dominate, before recent City signing Yasser Hussein was harshly adjudged to have fouled in the box.
Nicky Weaver pulled off a superb save to deflect Phil Edwards' powerful penalty over the bar, but the City keeper had to pick the ball out of the net a minute before the break as Jonathan Smith converted following another good save from Weaver.
In the 57th minute, Micah Richards pushed forward from defence to latch onto a Wright-Phillips flick-on and made it 3-1.
Fowler could have added another from Hussein's cross but was denied again, while Wigan were awarded another penalty in the 71st minute for a foul by Weaver. This time Smith took it and he claimed his second of the match.
Fowler was replaced with 15 minutes remaining, giving Stuart Pearce a welcome selection boost ahead of the derby.
“It’s great to have Nicky Weaver and Robbie Fowler back playing football,” reserve team coach Steve Wigley told the City website. “Robbie’s missed quite a bit of pre-season and we thought he’d go for 45 minutes and we ended up getting 75 from him."
Like the first team, City's second string are also unbeaten. In the league they've drawn 1-1 at West Brom and beat Middlesbrough 2-1 at home.
Last week they drew 0-0 against United in the Manchester Senior Cup.