In a statement, Genoa said that Under-17 coach Abdoulay Konko would be caretaker manager until the club finds a permanent replacement for the Ukrainian.
Former AC Milan and Chelsea striker Shevchenko had only won one of his 11 matches in all competitions after being hired by Genoa on 7 November, his team’s latest defeat coming against Milan in the Italian Cup on Thursday.
Under Shevchenko’s stewardship Genoa scored just three times in nine Serie A matches, failing to win any of them and losing six times.
Genoa, who were taken over by American backers 777 Partners in September, sit second-bottom in Serie A, five points from safety.
Shevchenko guided Ukraine to the Euro 2020 quarter-finals last summer, losing 4-0 to England in Rome.
The 45-year-old scored 175 goals in 324 matches in two spells with Milan, twice emerging as Serie A’s top scorer and winning a Serie A title and the 2003 Champions League.