Madrid moved above Valencia into third place in the table after Isco scored a free-kick and set up Casemiro against his old club.
The former Madrid midfielder could yet lead his side to Champions League glory for the third season in a row, although the La Liga title they won last term looks certain to go to rivals Barcelona this year.
Zidane's 100 victories give the Frenchman a win ratio of 71.4 per cent in his first senior role as a manager.
The win was Madrid's fifth in their last sixth Liga outings, with only Atletico Madrid denying Zidane victory with a 1-1 draw at the Bernabeu last week.
100 - Real Madrid have won their th game under Zinédine Zidane in all competitions (71.4% of wins). Master. pic.twitter.com/YejgFh9dDm— OptaJose (@OptaJose) April 15, 2018
The Merengue currently four points shy of their neighbours in the battle for second place, with Barcelona a further 11 points clear at the summit with just six games remaining in the season.