Zardari, along with his daughter and personal staff, flew from Dubai to Karachi in a special aircraft that landed in a Pakistan Air Force base in the southern port city shortly after 1 AM (local time).
The President drove in a motorcade from the airbase to Bilawal House, his family's private residence.
A sizeable number of policemen and security personnel were deployed along the route from the airbase to Bilawal House. Police also blocked traffic at key intersections along the route.
Manzoor Wasan, the home minister of Sindh province, told reporters that the President would stay at Bilawal House.
However, Wasan said he had no details of Zardari's itinerary or how long he intended to stay in Karachi.
The 56-year-old President's abrupt departure for Dubai on December 6 to seek treatment for what officials said was a heart condition triggered widespread speculation that he might quit due to pressure from the military establishment over a secret memo that had sought US help to help prevent a feared coup.
Zardari was admitted to the American Hospital in Dubai, where he underwent a battery of tests.
Doctors said the results of the tests were normal and advised Zardari to rest and recuperate.