Tsotsobe, with a career-best 3-16, and skipper Botha (3-31) led a spirited South African bowling to restrict Pakistan to a paltry 119 at the Abu Dhabi Stadium last night in a match whose income will go to flood victims in Pakistan.
Over two million people were displaced in the worst-ever floods in Pakistan.
Jean-Paul Duminy hit an elegant 41 while Colin Ingram remained unbeaten with 46 as South Africa reached the target after losing three early wickets for 26.
The two left-handers shared a solid 66-run partnership for the fourth wicket after paceman Shoaib Akhtar gave Pakistan some hope with the quick wickets of opener Loots Bosman and AB de Villiers in the third over.
Ingram hit two towering sixes and four boundaries during his 38-ball knock.
Duminy hit five boundaries as the two dominated the Pakistan bowling which initially looked threatening.
Botha said he was happy to lead the series."It was a clinical performance and I am happy at the way the young guns stepped in after we lost three early wickets especially Ingram and Duminy," said Botha.
Duminy, who also took two beautiful catches, was declared man-of-the-match.
Earlier, Tsotsobe and off-spinner Botha bowled tightly to derail Pakistan, who won the toss and batted on a flat pitch.
Misbah-ul-Haq, recalled after being axed following the World Twenty20 in May this year, topscored with 27 with a six and two boundaries.Skipper Shahid Afridi hit a rapid seven-ball 25 before he became one of Botha's three victims.Pakistan had raced to 16 in the second over before Tsotsobe removed openers Imran Farhat (10) and Shahzaib Hasan (nine) in the sixth.
Botha then removed Mohammad Hafeez (13), Afridi and Abdul Razzaq (four) to end Pakistan's hopes of reaching a respectable total.Pakistan coach Waqar Younis was disappointed over the poor batting.
"We scored 25-30 runs less than we expected," said Waqar, whose team lost the last six wickets for a mere 35 runs."We need to bat with strategy in the next game."
This is Pakistan's home series shifted to United Arab Emirates due to security fears.
The two teams meet in the second Twenty20 here today.
They then play the first two one-day internationals and the second Test in Abu Dhabi. Dubai will stage the last three one-day and the first Test.
Shahzaib Hasan c Duminy b Tsotsobe 9
Imran Farhat c Smith b Tsotsobe 10
Mohammad Hafeez c Ingram b Botha 13
Umar Akmal c Botha b A.Morkel 14
Shahid Afridi c Bosman b Botha 25
Misbah-ul-Haq not out 27
Abdul Razzaq b Botha 4
Zulqarnain Haider c Duminy b M.Morkel 1
Umar Gul c Smith b Tsotsobe 0
Saeed Ajmal run out 4
Shoaib Akhtar run out 3
Extras: (LB-1, NB-3, W-5) 9
Total (all out, 19.5 overs) 119
Fall of wickets: 1-16, 2-38, 3-46, 4-75, 5-84, 6-90, 7-91, 8-92, 9-99.
Bowling: M Morkel 4-0-28-1, Tsotsobe 4-0-16-3, A Morkel 4-1-18-1, Theron 3.5-0-25-0, Botha 4-0-31-3.
G Smith b Hafeez 13
L Bosman c Farhat b Akhtar 2
AB de Villiers b Akhtar 0
J Duminy c Akmal b Ajmal 41
C Ingram not out 46
D Miller not out 13
Extras: (LB-3, W-2) 5
Total: (for four wickets, 18.2 overs) 120
Fall of wickets: 1-16, 2-16, 3-26, 4-92
Bowling: Akhtar 4-1-29-2, Razzaq 2-0-20-0, Hafeez 3-0-10-1, Gul 3.2-0-17-0, Ajmal 4-0-18-1, Afridi 2-0-23-0.