[3][4] Starting the 2004–05 season for Roma, he left the team because of personal problems involving his wife, with her being seriously ill. Prandelli joined Fiorentina as manager in the summer of 2005.

In Serie A, the team finished fourth after winning a long race against Milan, earning a ticket to participate in the 2008–09 Champions League following a season in which his wife died.

In 2009, Prandelli surpassed Fulvio Bernardini as the longest-serving manager in Fiorentina history, and guided the viola to a historic qualification in the round of 16 of the 2009–10 Champions League, where it was eliminated by Bayern Munich (which later went on to reach the final) through the away goals rule.

Prandelli, however, did not manage to repeat such successes at the domestic stage, with things being made even more complex by his key player Adrian Mutu being suspended due to doping-related issues.

On 20 May 2010, Fiorentina confirmed that Prandelli was given permission to hold talks with Italian Football Federation (FIGC) president Giancarlo Abete to replace Marcello Lippi as head coach of the Italy national team after the 2010 FIFA World Cup.

[12][13] Under Prandelli, Italy went on to finish third in the 2013 FIFA Confederations Cup in Brazil, beating out Uruguay 3–2 in the penalty shootout after a 2–2 deadlock following extra time in the bronze medal match.

[17] After comfortably guiding the Italian team to qualification to the 2014 World Cup, in March 2014 it was revealed Prandelli had agreed a two-year contract extension that would keep him in charge until Euro 2016.

[20] On 24 June 2014, Prandelli resigned as Italy manager after a controversial 1–0 defeat against Uruguay in their final group match, which eliminated Italy from the World Cup in the group stage; during the match, Claudio Marchisio was sent off and the referee Marco Antonio Rodríguez failed to see Luis Suárez bite Giorgio Chiellini prior to Uruguay's goal from a corner kick.

[23][24][25] On 3 July 2014, Prandelli became the manager of Galatasaray taking over from the previous fellow Italian coach Roberto Mancini, signing a two-year contract.

His league performance was certainly not bad: in ten weeks his team managed to get six wins, one draw and three losses, landing at third place in the Süper Lig, one point behind Fenerbahçe and Beşiktaş.

[34] He resigned on 23 March 2021 following a 2–3 home loss to AC Milan, declaring on a public statement his decision to be motivated by personal reasons and a feeling of distress, and also hinting at the fact it might have been his final role as a coach in his career.

[35][36] As manager of Fiorentina, Prandelli made use of a 4–4–2 formation; the team's style of play was based on pace and ball-distribution, rather than physical power, with a centre-forward being supported by a second striker up-front.

[38] During his time as manager of the Italy national football team, Prandelli was known for his offensive tactics and for implementing an attractive playing style based on passing and ball possession, which was likened to Spain's tiki-taka.

[12][13][39][40][41][42][43][44][45] In Italy's opening match against Spain, Prandelli used defensive midfielder Daniele De Rossi as a ball-playing centre-back in a back-three, due to injuries to his team's starting defenders.

[52] Prandelli was also known for implementing a strict ethical code during his time as Italy manager, excluding players who had been suspended due to violent conduct or poor behaviour.

Prandelli's son Nicolò has also embarked on an off-pitch football career, having been chosen as a fitness coach by Parma in 2009,[55] and then by the Italy national team during the buildup to the Euro 2012 finals.