Khan, an 88-Test veteran who needs five wickets to reach the 300 mark, had not been considered since the third Test against England in Kolkata a year ago due to form and fitness issues.
The 35-year-old was not handed a central contract this season, but found favour with the selectors after he claimed 13 wickets in three Ranji Trophy first-class matches for Mumbai, including a five-wicket haul.
Khan will spearhead a five-man seam attack in South Africa where he claimed 10 wickets in two Tests on the previous tour in 2010-2011.
But the left-arm seamer was not selected for the three-match one-day series against the Proteas which starts on December 5 and precedes the Tests.
Gambhir, who was also sidelined after the home series against England, failed to impress the selectors despite making 153 on a green-top on Saturday to fashion Delhi's Ranji Trophy win over Haryana.
Tendulkar, the world's leading run-getter in both Test and one-day cricket and the only batsman to score 100 international centuries, retired after playing his 200th Test earlier this month.
The tour opens with the first one-day international at the Wanderers in Johannesburg on December 5. The remaining two one-dayers will be held in Durban (Dec 8) and Centurion (Dec 11).
India will play a two-day warm-up match in Benoni on Dec 14-15 ahead of two back-to-back Tests in Johannesburg (Dec 18-22) and Durban (Dec 26-30).
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