Hayen is paying the price for his team's poor results in the league, with three defeats in their last four matches, the latest a 3-2 reverse at Sint-Truiden on Saturday.
The result dropped the Belgian champions to third in the table, five points behind leaders Union Saint-Gilloise and one behind Sint-Truiden.
Club Brugge are also struggling in the Champions League with four points and only one win, a fine 4-1 victory over Monaco in September, in five games, leaving them 26th in the standings.
Hayen, who had been in the job for a year and a half and won the domestic title last season, is replaced by Leko, who had been managing Gent since the start of the season.
The 47-year-old, who won 13 caps for Croatia, played 98 times for Club Brugge winning the Belgian Cup in 2006-07. He also had a previous stint as manager winning the league in 2017-18.