It is the first time that the former president, who will be staying with his daughter in Karachi, has left Islamabad after being indicted in a high treason case by a special court last month.
Musharraf is due to appear in court in person in Islamabad on Monday in the murder case of a slain Baloch nationalist leader, or face arrest.
But his aides insisted his visit to Karachi had been pre-planned.
“He was planning to spend some time with his daughter there as his wife is in Dubai taking care of his ailing mother,” Afshan Adil, a close aide and lawyer told AFP.
“He is also supposed to undergo some diagnostic tests in a Navy-run hospital there,” she added.
It was unclear whether Musharraf would return to the federal capital for the Monday court hearing.
Musharraf left his heavily guarded farm house in Islamabad around 7:00 pm (1400 GMT) on Saturday evening.
Two armoured vehicles escorted him to the airport, with surrounding roads closed to the public and a heavy contingent of rangers and police deployed along the route.
An AFP photographer at Islamabad airport said rangers had taken control of the area and the VVIP lounge evacuated before Musharraf’s arrival.