Former captain Cook stood firm as the historic occasion was frustratingly interrupted by four stoppages, resisting throughout the day to finish unbeaten on 82 as wickets tumbled around him.
The 32-year-old negotiated a demanding examination from a South African pace attack inspired particularly by two-wicket Vernon Philander, who also spent 50 minutes off the field with a stomach upset, to close in on a 31st test hundred.
With the four-test series locked at 1-1, the visitors made light of losing the toss with Cook, who survived 178 balls, and Philander, who had excellent figures of 2-17 from 12 overs, proving the central figures.
Electing to bat, England captain Joe Root gave his predecessor Cook the chance to impress again in the landmark test at the south London venue which has become one of cricket's most historic grounds over 137 years.
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The Oval joined another London venue Lord's and Australia's Melbourne and Sydney Cricket Grounds in hosting a century of tests.
In a new-look England side, featuring three new caps, batsmen Tom Westley and Dawid Malan and seamer Toby Roland-Jones, it was old stager Cook whose summoned all his skill and resolve to anchor the innings in conditions assisting the Proteas' pacemen.
In an awkward morning session in overcast conditions and with a green tinge to the pitch, South Africa's attack did not initially pose the menace they had shown in their 340-run victory at Trent Bridge, which levelled the series.
CAPABLE SUPPORT
Cook was given capable support by Essex county colleague Westley in a half-century stand before lunch but the newcomer departed for 25 straight after the resumption, pushing hard at Chris Morris to edge to second slip.
Westley had impressed after Keaton Jennings was again found wanting, prodding tentatively at Philander to be caught at third slip for a duck in the fourth over.
Cook, on 28, survived an lbw review, the faintest of inside edges off Morris sparing him, but otherwise looked his usual model of serenity as he made it to an early lunch, after two rain stoppages, on 34 with England at 62 for one.
The South Africans imposed more pressure on the resumption with Philander dismissing the dangerous-looking Root for 29, thanks to a dazzling, diving one-handed catch from wicketkeeper Quinton de Kock.
Kagiso Rabada, back in the team after suspension, then sent debutant Malan packing for one with a lovely inswinging yorker.
Still, though, Cook ploughed on after another rain break, maintaining his focus to bring up his half-century off 128 balls with a handsome cut for four off Philander.
Tea was taken early at 149 for four after another stoppage and though Cook and Ben Stokes repaired some of the damage with an unbroken 51-run partnership for the fifth wicket, a fascinating day's play ended up being truncated by another downpour.
(Reporting by Ian Chadband, editing by Ed Osmond)
