Sherry Rehman, an ally of President Asif Ali Zardari, who has been ambassador to Washington since late 2011, has been accused of blasphemy over remarks she made on a chat show in 2010.
Those found guilty of defaming the Prophet Mohammed in Pakistan can be sentenced to death. People facing similar accusations in the past have been forced into hiding or even killed by lynch mobs.
In late 2010 Rehman sparked fury among religious groups as a lawmaker by lodging a private member's bill seeking to abolish the death penalty for blasphemy after a Christian mother of five was sentenced to death.
Her fellow campaigner, PPP politician Salman Taseer, was murdered in January 2011. Two months later, minorities minister Shahbaz Bhatti was also killed.
For nearly three years, Muhammad Faheem Akhtar Gill, a marble dealer in the central city of Multan, has tried to persuade police to register a case against her for allegedly making blasphemous remarks on a chat show in late 2010.
On Tuesday, police confirmed that they had started investigations on the order of the Supreme Court, according to a court document obtained by AFP.
"I am investigating the case on the orders issued by the court," senior police official Ghulam Shabbir Jaffri told AFP in Multan on Thursday.
"It is a three-member committee and we are doing the inquiry."
Gill said he would appear before the committee on Saturday to record his statement and that of his witnesses.
A lawyer representing Rehman, Abid Hasan Minto, told AFP an appeal had been filed in the Supreme Court against the order to investigate the case.
The police investigation is the latest case to highlight the sensitivity of blasphemy in Pakistan, where 97 percent of the population are Muslims.
Last December, an angry mob stormed a police station in the south, beating to death a man held for allegedly desecrating the Koran.
Last year, Pakistan's blasphemy laws drew worldwide attention when a Christian girl was accused of burning papers printed with verses from the Koran.
She spent three weeks on remand in one of Pakistan's toughest prisons before a court threw out all charges against her.