In January 1960, he was transferred to Manchester United for a fee of £30,000. Matt Busby signed Setters as a replacement for the injured Wilf McGuinness who had suffered a career ending leg break. Setters developed his reputation for being one of footballs 'hard men' and his combative style made him a key part of the team. A poor 1962–63 league campaign saw Manchester United nearly relegated in the Second Division but they did beat Leicester City 3–1 in the 1963 FA Cup Final. A much improved 1963–64 season brought a 2nd-place finish behind Liverpool. A 7–0 win over Aston Villa early in the 1964–65 season was Setters 159th and final game for Manchester United as he was sold to Stoke City for £30,000.