A former player with only two Serie A seasons (both with Torino) in his career, Mondonico had a much more successful career as a manager. After two years as youth coach with Cremonese, he became the team's head coach in 1981, guiding the club into promotion to the top flight in 1984. Another promotion followed in 1988 with Atalanta, another former team of him as a player, which then he successfully guided to the semi-finals of the UEFA Cup Winners' Cup 1988–89.
In 1990 he joined Torino, guiding them to fifth place and to a historic UEFA Cup final in 1991–92, then lost to AFC Ajax in a controversial game that became famous for Mondonico clearly lifting up a chair into the air in a sign of protest against the referee. In 1993, he led Torino to victory in Coppa Italia, in which they defeated Roma on the away goals rule after the two teams tied at 5–5 in the two-legged final.
On 2004, he replaced Alberto Cavasin as the head coach of ACF Fiorentina, which had just been admitted to play Serie B directly from Serie C2 by the federation. Despite all of this, Mondonico managed to qualify in a two-legged promotion playoff, winning it to Perugia. Mondonico headed Fiorentina also to Serie A, but was successively fired and replaced by Sergio Buso.
In January 2006, he accepted the offer of U.C. AlbinoLeffe, a minor Serie B team which was involved in a relegation battle and second-last placed at the time of his signing. Mondonico was able to lead AlbinoLeffe to qualify to a relegation playoff, winning it to U.S. Avellino. Mondonico was confirmed at the helm of AlbinoLeffe also for the 2006–07, leading the small club to a record 10th place in the Serie B. In June 2007 he left AlbinoLeffe to join Cremonese of Serie C1 in a somewhat surprise move, but missed to guide his side back to Serie B after losing the promotion playoff finals to Cittadella. He then left the club by mutual consent, only to return to Cremonese in December 2008 to replace Ivo Iaconi; he successively resigned in March 2009 after a string of poor results.
On September 2009 he was appointed back at AlbinoLeffe to replace Armando Madonna. He stepped down as head coach of AlbinoLeffe on 29 January 2011 due to "serious health issues", with his assistant Daniele Fortunato taking over on an interim basis. Two days later, his club confirmed he had undergone abdominal surgery, expecting him to recover in a few weeks time. On 15 February, after a full recovery, Mondonico officially returned to his coaching duties at AlbinoLeffe. He guided AlbinoLeffe to narrowly escape relegation after defeating Piacenza in the playoffs, but on 13 June he held an emotional press conference to announce that the illness had returned during the final period of season and that he was seriously considering stepping down as a consequence. On 17 June 2011 Mondonico was confirmed to have resigned from AlbinoLeffe in order to focus solely on cancer treatment; he was replaced by his assistant Daniele Fortunato, who already took first team coaching duties during his previous sick leave. A few months later he announced to have defeated cancer, and also stated to be ready to get back into work.
On 30 January 2012, Mondonico marked his Serie A comeback, replacing Attilio Tesser as head coach of Novara, last-placed in the Italian top flight and seven points shy of relegation safety after the first season half. On 6 March 2012 he was sacked.