On 18 January 2016, Guidolin was named head coach of Swansea City, at that point struggling in the 2015–16 Premier League, only two points above the relegation zone, to work alongside interim manager Alan Curtis, who took the post of first team coach. While the decision baffled some pundits, the Swansea chairman argued that Guidolin's achievements at Udinese on a relatively small budget were similar to what the club was trying to achieve. At the time of his appointment, Guidolin was virtually unknown to the English game and club captain Ashley Williams later admitted that he had to "Google" his new manager.
Guidolin took charge of his first game on 24 January 2016, an away fixture at Goodison Park which Swansea City won 2–1, recording the club's first-ever league win over Everton. On 1 May, Guidolin mathematically secured Swansea's place in the Premier League for the following season, as the club defeated Liverpool 3–1 at Liberty Stadium. On 11 May 2016, and despite intense speculation and betting that former manager Brendan Rodgers would replace him, Guidolin was invited to sign a new two-year-contract with Swansea after impressing the club's board of directors with his achievements in the late winter and spring of the 2015–16 season.
After a poor start in the Premier League the following season, Guidolin was sacked on 3 October 2016, his 61st birthday, and replaced with immediate effect by former United States national team manager Bob Bradley.