Saleem Altaf, director cricket operations, said Malik had been ruled out with a knee injury while Yousuf would miss the first Test to be with his pregnant wife.
The first Test starts on Jan. 11 in Johannesburg.
''Yousuf might even miss the second Test as his wife has a complicated pregnancy and her operation could be delayed until the 19th,'' Altaf told Reuters.
Yousuf was Pakistan's most successful batsman last year scoring 1,788 runs with nine centuries, breaking the 30-year record for most runs and hundreds in a calender year set by West Indian Viv Richards.
Altaf said Malik had been advised to take two weeks rest.
''Umar Gul is also suffering from an ankle problem and will undergo Tests when the team reaches Johannesburg on Tuesday,'' said Altaf.
''We are not sure if he was carrying the ankle injury when he went to South Africa. But his position will become clear after the Tests,'' he added.
All-rounder Abdul Razzaq has already been ruled out of all three Tests with a calf muscle injury.