Jayawardene shared a record eighth-wicket partnership for Sri Lanka of 170 runs with Chaminda Vaas (69), surpassing the 146 scored by Upul Chandana and Thilan Samaraweera against Zimbabwe in 2002.
Sri Lanka, who had resumed on 279-7 having lost two wickets in the last two overs of Wednesday, took control of the match on a dry pitch.
South Africa, missing their skipper and only specialist opener Graeme Smith, who was laid low with a virus, were on 82 without loss at close of play.
Boeta Dippenaar survived a television referral for a stumping and was unbeaten on 46 with Martin van Jaarsveld 30 not out.
Jayawardene, starting the day on 116, was in imperious form, dominating an increasingly weary South African attack during a chanceless eight-and-a-half hour marathon.
The 27-year-old right-hander faced 415 balls, hitting 25 fours and three sixes.
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South Africa's fielders believed Jayawardene had been caught off the glove on 190 but replays showed the ball had hit his arm.
Jayawardene raced to the second double hundred of his career, sweeping Nick Boje for four and then reached the landmark with a straight six two balls later.
Vaas hit 10 boundaries during his 142-ball 69 before drilling a catch to mid-off where Nantie Hayward took the catch on the second attempt.
Jayawardene was finally trapped lbw by Hayward, who then bowled Muttiah Muralitharan first ball to wrap up the innings a few minutes before the tea break.
Hayward finished with three wickets for 81 runs but Pollock was South Africa's best bowler, with four for 48 from 23 overs.
Scorecard:
Sri Lanka first innings (overnight 279-7)
M.Atapattu c Boucher b Pollock 9
S.Jayasuriya c Klusener b Pollock 12
K.Sangakkara c Boucher b Boje 58
M.Jayawardene lbw b Hayward 237
T.Samaraweera lbw b Pollock 13
T.Dilshan b Hayward 25
R.Kaluwitharana b Pollock 33
U.Chanadana b Ntini 5
C.Vaas c Hayward b Boje 69
M.Maharoof not out 6
M.Muralitharan b Hayward 0
Extras (b-8 lb-3 nb-6 w-2) 19
Total (all out, 145.4 overs) 486
Fall of wickets: 1-13, 2-22, 3-108, 4-145, 5-189, 6-274, 7-279, 8-449, 9-486
Bowling: Pollock 23-5-48-4 (nb-4), Ntini 20-1-61-1, Hayward 16.4-0-81-3 (nb-2), Kallis 16-3-52-0, Klusener 19-0-69-0, Boje 42-3-148-2 (w-2), Rudolph 9-2-16-0
South Africa first innings:
B.Dippenaar not out 46
M.van Jaarsveld not out 30
Extras (b-4 lb-2) 6
Total (for no wicket, 34 overs) 82
To bat: J.Rudolph, G.Smith, J.Kallis, L.Klusener, S.Pollock, M.Boucher, M.Ntini, N.Hayward, N.Boje
Bowling (to date): Vaas 8-3-20-0, Maharoof 7-4-9-0, Muralitharan 12-1-36-0, Chandana 6-0-10-0, Jayasuriya 1-0-1-0
