With the help of the attacking partnership of Antonio Cassano and Giampaolo Pazzini, he led the team to qualify for the UEFA Cup in his first season and subsequently reached the Coppa Italia final the next year.

In May 2007, Mazzarri was made an honorary citizen of Reggio Calabria, after helping the club avoid relegation during the 2006–07 Serie A season.

[4] He served as Sampdoria boss for two seasons, overseeing a considerable improvement in results, thanks to the likes of the attacking duo of Antonio Cassano, who publicly praised Mazzarri's coaching abilities, and Giampaolo Pazzini; the duo were likened to the partnership of Roberto Mancini and Gianluca Vialli, who won the scudetto with the club in 1991.

Napoli won 3–1 at home in the first leg; they were subsequently beaten 4–1 at Stamford Bridge after extra time, being eliminated by the eventual champions.

[19] On 11 August that year, the club suffered a controversial 4–2 extra-time defeat to Juventus in the 2012 Supercoppa Italiana, which saw two Napoli players sent off as well as Mazzarri.

[29] Mazzarri secured Watford's Premier League status that season, finishing one place above relegation in 17th, a four-place dip on their previous campaign.

[33][34] On 15 September 2021, Mazzarri signed a three-year contract with Serie A club Cagliari as their new head coach, replacing Leonardo Semplici.

[35] During his tenure, Cagliari failed to improve performances and found themselves deep in relegation trouble with three games to go, leading to Mazzarri's dismissal from his position on 2 May 2022.

[38] Tactically, Mazzarri is known for using a fluid attacking 3–4–3 formation as a manager; at Napoli, his effective front three of Lavezzi, Hamšík, and Cavani were dubbed I tre tenori ("The Three Tenors").

[42] Although he earned a reputation as one of the best coaches in Serie A during the early 2010s,[43] Mazzarri also became known in Italy for the excuses he made for poor performances during post-match interviews.