Interior Minister Miguel Angel Osorio Chong gave no reason for the resignation of Manuel Mondragon y Kalb, who he said would remain in government.
"I accepted a request by (Mondragon y Kalb) to retire from the field of operations," Osorio Chong wrote on Twitter.
However Mondragon y Kalb will continue to work with the ministry on strategy, said Osorio Chong, who thanked the veteran official "for his efficient and patriotic work."
A formal announcement will be made on Tuesday, the message said.
The National Security Commission (CNS), which falls under the interior ministry, was created by President Enrique Pena Nieto in January 2013 to replace the Secretariat of Public Security.
The CNS, in charge of the Federal Police, is behind schedule in its task to create a paramilitary anti-drug National Gendarmerie, one of Pena Nieto's key campaign promises.
More than 77,000 people have been killed since former president Felipe Calderon (2006-2012) deployed soldiers to crack down on Mexico's violent, well-armed illegal drug cartels.