He told radio station WKAQ that he's leaving for personal reasons, but did not elaborate.
"It was time to go," he said during the interview. "For the past 19 months, I have given it my all and I go with my head held high."
During his tenure, the number of killings subsided somewhat, with 749 killings reported so far this year compared to 794 in the same period last year.
Rep. Jose Aponte, former speaker of the island's House of Representatives and a member of the main opposition party, said in a phone interview that Pesquera helped instill trust again in Puerto Rico's police officers.
"His departure at this time goes against the best interests of Puerto Rico," he said. "The job he did was good, it was effective."
Pesquera is leaving as Puerto Rico prepares to fight an increase in drug trafficking, with federal authorities noting an uptick in the number of cocaine seizures and other drugs. Police have said at least 75 percent of killings in the U.S. territory are tied to drug trafficking.
The police department also faces a multimillion dollar, 10-year federal reform that will see numerous changes, including the creation of new disciplinary procedures, a use-of-force policy and additional training for officers before they're assigned to the streets.