Antlers, who are looking to win the continental title for the first time, took the lead two minutes before the hour mark when Leo Silva picked the ball up on the edge of the area before firing a low left-foot shot into the bottom corner of Alireza Beiranvand's goal.
Twelve minutes later, Serginho scored his fifth goal in five Asian Champions League games since joining Kashima in the summer from Santos when he latched on to Kento Misao's through ball to beat Beiranvand and leave Persepolis facing a tough challenge in the second leg.
"Looking at the second half, it was the ideal performance from my team," said Kashima coach Go Oiwa.
"But this is only the first half of a game of 180 minutes and we want to concentrate on the next game, not only in the Asian Champions League but we also have a domestic league game as well so we just want to keep going."
Kashima struggled for fluency in the opening 20 minutes but the eight-time Japanese champions asserted themselves as the game wore on.
Leo Silva's opener gave Beiranvand little chance in the 58th minute and the first-leg result was put beyond any doubt in the 70th minute when Serginho's shot beat Iran's World Cup goalkeeper after the Persepolis defence failed to clear.
The Iranian side's hopes were hit further by Siamak Nemati's sending off in injury time for a second bookable offence, meaning the midfielder will miss the return at the Azadi Stadium next Saturday, when the teams will face off in Tehran in front of an expected crowd of more than 80,000 fans.
"This is a good result for the Kashima team, 2-0 is a big result," said Persepolis coach Branko Ivankovic.
"But we showed what we can do. I expect and we hope that we will be better than today. We will try to do our best. It won't be easy. If it was 1-0 or 0-0 it would be the same because Kashima play the same way away from home." (Reporting by Michael Church, Editing by Amlan Chbakraborty)
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