In the diplomatic cables, Carlos Pascual complained about Mexico's inefficiency in the government fight against drug cartels and reported infighting among Mexican security forces.
Mexican President Felipe Calderon has publicly criticized the leaked Pascual cables.
Pascual's resignation comes less than two weeks since President Barack Obama met with Calderon at the White House. It appeared to be the biggest fallout yet from thousands of sensitive U.S. diplomatic cables from around the world released by WikiLeaks.
Mexico's government offered a polite and muted response, offering "its best wishes to Ambassador Carlos Pascual in the duties he will undertake after concluding his post in our country."
Pascual is the Obama administration's first U.S. ambassador to publicly depart his post.
The Associated Press contributed to this report.