Setters started his career with Exeter City making his debut towards the end of the 1953–54 season. He made ten appearances for the "Grecians" in 1954–55 and impressed enough to tempt First DivisionWest Bromwich Albion to acquire his signature in the summer of 1955. Under the guidance of Vic Buckingham Setters became a regular as the "Baggies" finished in 4th in 1957–58 5th in 1958–59 and 4th again in 1959–60. Setters was included in England's 1958 FIFA World Cup squad as a reserve player, but did not travel to the tournament or play in any matches. 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 earned him the captaincy. 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 final game for Manchester United as he was sold to Stoke City for £30,000. He played 19 times for Stoke in 1964–65 as Stoke claimed a mid-table finish of 11th position. At the end of the campaign, with the squad training for their pre-season in the United States Setters was involved in a 'bust-up' with teammate Calvin Palmer. Setters apologised to manager Tony Waddington and was allowed to travel to the United States but Palmer did not apologise and was forced to stay in England. Out in America, Setters played nine times for the Cleveland Stokers scoring three goals. He missed just three matches in 1965–66 playing in 45 fixtures. His run in the first team continued in 1966–67 until he sustained injury against Liverpool on 4 March 1967 which allowed Alan Bloor to take his place. After failing to dislodge Bloor, Setters joined Coventry City in November 1967. He made 59 appearances for Coventry in just under three years at Highfield Road and ended his career with a four-month spell with Second Division Charlton Athletic.
Managerial career
Setters spent three and half years as Doncaster Rovers manager in the early 1970s before becoming Jack Charlton's assistant at Sheffield Wednesday in 1977. When Charlton resigned on 27 May 1983, Setters stayed on as caretaker manager for four weeks, although the club played no matches during this period. He later linked up with Jack Charlton again from 1986 to 1995 as assistant manager with the Republic of Ireland senior squad.