The Venezuelan put the league leaders in front with a header in the closing stages of the first half, before doubling his tally with a driven effort from a tight angle after 70 minutes.
Rondon made it three eight minutes later with a composed close-range finish, becoming the league's top goalscorer on 10 with his second treble of the campaign.
The attacker's hat-trick comes on the back of a brace in a 3-0 win over PSV in the UEFA Europa League last month, which sent Zenit into the last 16 with a 4-0 aggregate victory.
Zenit remain seven points clear of CSKA Moscow, who were 2-1 winners at Terek Grozny - Ahmed Musa's double either side of an Igor Lebedenko effort earning maximum points.
Dinamo Moscow's 3-1 win over Ufa sees them stay within two points of CSKA, while Krasnodar earned a first win in three with a 3-1 triumph at Spartak Moscow.
Rostov remain rooted to the foot of the table thanks to a 1-0 defeat at home to Lokomotiv Moscow, but are level on points with Arsenal Tula, who lost 1-0 to Rubin Kazan.
Amkar Perm's goalless draw against Torpedo Moscow edged them two points clear of the automatic relegation zone, while Mordovia Saransk held Kuban Krasnodar to a goalless draw.
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