Wolvaardt struck 124 from 111 balls while Luus scored 114 off 113 deliveries and Dane van Niekerk hit 88 off just 47 balls as the home side blazed their way to 375-6 in their 50 overs.
Chasing a mammoth target, Ireland fought bravely with the bat before being eventually being bowled out for 301 in 47.5 overs.
Having won the toss and and elected to bat, Wolvaardt watched on as Tazmin Brits (6) and Lara Goodall (12) lost their wickets within the first 11 overs as the Proteas Women were 59-2.
The skipper and Luus then combined for a 179-run partnership that set the platform for the huge total that followed.
Wolvaardt went on to score her 12th ODI century while for Luus it was a second hundred in the format.
Van Niekerk then created carnage in the death overs as the former captain plundered 13 fours and three sixes in her whirlwind innings to take the Proteas Women beyond the 370-mark for the first time in 50-over cricket.
Orla Prendergast struck a fine 86-ball 97 for Ireland in response while Amy Hunter hit 64 and Gaby Lewis 45 but it was never going to be enough.
Proteas Women seamer Leah Jones on ODI debut returned respectable figures of 3-48 while spin twins Nondumiso Shangase and Miane Smit took two wicket apiece.
The hosts will be aiming for a series clean sweep with the final game set to take place at the Wanderers on Friday.
Miane Smit struck a maiden fifty while Sune Luus also struck an unbeaten half-century as the Proteas Women cruised to a seven-wicket win in the opening ODI against Ireland at Buffalo Park in East London.
Captain Laura Wolvaardt struck a record-breaking century to help the Proteas Women thrash Ireland by 105 runs in the first of three T20Is played at Newlands on Friday.
Dane van Nierkerk is set to return to international cricket after an absence of more than four years after being included in the Proteas Women's squads for the white-ball series at home against Ireland.
There was double delight for South Africa after Proteas Women's captain Laura Wolvaardt and men's spinner Senuran Muthusamy scooped the ICC player of the month awards for October.
