Guidolin's managerial debut came in 1988 as head coach of Serie C2 team Giorgione, the main club of his native city, Castelfranco Veneto.

During the 1996–97 season, Vicenza led the league for a period, eventually achieving an eighth-place finish in Serie A, and won the 1997 Coppa Italia, defeating Napoli 3–1 on aggregate in the two-legged final.

The following league campaign ended with another ninth-place finish, followed by another small improvement to seventh place and entry into in a summer tournament, the 2002 UEFA Intertoto Cup, where they were defeated in the three-game final stage by Fulham.

Playing Luca Toni as a lone striker among experienced players and those cast off from larger teams, he won the division, taking the Sicilians back to the top flight for the first time since 1973.

The season was also disrupted when the club was one of the two teams involved in the Sicilian derby of 2 February 2007 which led to riots and a police fatality, resulting in various safety restrictions being imposed on the league.

[11] In October 2007, Guidolin declined to take up an offer to coach struggling English Championship side Queens Park Rangers after failing to agree personal terms.

[15] On 30 September 2008, Guidolin signed a contract with Serie B side Parma, guiding them to second place in the 2008–09 campaign, earning promotion back into the top flight.

Despite the manner of his departure from Palermo, he is still today hailed as one of the club legends and was warmly welcomed during his return as Parma manager, albeit suffering a late defeat to his old side.

[24] 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.

[25] 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.

[22] 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.

[27] 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.

[36] At Vicenza, Guidolin used several systems, but predominantly fielded a fluid 4–4–2 formation with overlapping full-backs, and switches of play to utilise the width of the pitch.

Balance was also an important part of his system; as such he complemented the attacking play of winger Gabriele Ambrosetti with the use of a defensive full-back Lorenzo Stovini, who would cover for the former.

Guidolin also utilised his players' versatility (such as Gustavo Méndez, Zauli, Davide Belotti, and Massimo Beghetto), deploying them in different positions throughout the course of the season, depending on their opponent.

[37] During his time as head coach of Udinese, Guidolin was instead known for playing an aggressive, and attractive attacking style of football, primarily based on possession;[34][38][39][40][41][42] however, his team were also capable of creating chances and scoring from counter-attacks with few touches.

[46][47] At Swansea, Guidolin also maintained an energetic, free–flowing approach based on ball possession and passing, in a similar manner to that used by several of his predecessors at the club, Roberto Martínez, Brendan Rodgers, and Michael Laudrup.