Klusener, batting at No 9, launched a ferocious assault on a tiring attack as he and the more sedate centurion, Brian McMillan, broke a 95-year-old mark to set an eighth-wicket record partnership of 147 in South Africa's 529 for 7 declared.
Facing a tricky 16 overs to the close, India's reply began disastrously when Woorkeri Raman was run out for five by Klusener, who then completed an unforgettable day by bowling Rahul Dravid in his first over.
With Paul Adams following up with the wicket of nightwatchman Venkatesh Prasad for a duck, India were 29 for 3 at the close still needing a further 301 to avoid the follow-on.
South Africa had already been put in a strong position by Klusener and McMillan, whose 147 in 140 minutes eclipsed the country's previous record of 124 set in 1902-03 by A W Nourse and E A Halliwell against Australia in Johannesburg.
The total was South Africa's highest since their readmission to the Test scene and their best against India. It was only the second time three South Africans had scored centuries in the same Test innings following Gary Kirsten's 103 on the first day.
A day of records also included a record stand for the seventh wicket against India of 83 between McMillan and Dave Richardson (39).
India face a long haul to get back into the series, having lost the first of the three Tests by 328 runs.
(Second day; South Africa won toss)
SOUTH AFRICA - First innings
(Overnight: 280 for 4)
*W J Cronje c Mongia b Srinath 41
B M McMillan not out 103
S M Pollock c Tendulkar b Prasad 1
D J Richardson c Dravid b Srinath 39
L Klusener not out 102
Extras (b5 lb9 nb8) 22
Total (for 7 dec, 162.5 overs) 529
Fall (cont): 5-291 6-299 7-382
Did not bat: A A Donald, P Adams
Bowling: Srinath 38-8-130-3; Prasad 36-1-114-3; Ganesh 23.5-6-93-0; Kumble 51-7-136-0; Ganguly 9-1-24-0; Raman 5-1-18-0
INDIA - First innings
W V Raman run out 5
R S Dravid b Klusener 2
S Ganguly not out 19
V Prasad b Adams 0
*S R Tendulkar not out 1
Extras (nb-2) 2
Total (for 3) 29
Fall: 1-7 2-24 3-25
To bat: N R Mongia, M Azharuddin, V V Laxman, A Kumble, J Srinath, D Ganesh.
Bowling: Donald 6-3-7-0; Pollock 5-1-15-0; Adams 3-1-3-1; Klusener 2- 1-4-1.
Umpires: D Hair (Aus) and R Koertzen (SA).