The England and Wales Cricket Board revealed the original idea for this 100-ball tournament three years ago and finally it became a reality with 7,395 spectators in attendance at the Kia Oval.
While the format comes with plenty of new rules, some things remain the same and Van Niekerk's half-century saw Invincibles chase down a target of 136 for victory by five wickets and with two balls to spare.
It capped a memorable evening in the capital with Marizanne Kapp, Van Niekerk's wife, also claiming the honour of taking the first wicket despite getting proceedings started with a leg-side wide, but the cricket improved from that point onwards much to the delight of a youthful crowd.
While Originals captain Kate Cross called correctly at the toss and choose to bat first, the opening run of the competition occurred via an extra once fireworks and flame throwers had gone off at the Kia Oval.
Kapp got proceedings under way with a leg-side wide before the first run from the bat went to visiting opener Lee following a pull down to fine leg which almost went to the boundary after Shabnim Ismail initially misfielded.
The South African bowler did make more history soon after, having taken advantage of the chance to bowl 10 consecutive balls, as with her seventh legal delivery Emma Lamb was caught behind by Sarah Bryce for a duck.
Umpire Tim Robinson had made a surprise not-out call, but a review brought about the first wicket of The Hundred before the runs started to flow.
Kapp claimed another maximum through cow corner soon after, but – like in the three years from the point this tournament's concept was unveiled – more twists and turns were on the way with the South African stumped the very next ball by Ellie Threlkeld off Ecclestone.
But Van Niekerk was able to bring up her half-century, the first of the competition with another sumptuous boundary and then Villiers showed her ability with the bat thanks to a timely maximum.
The local fans in attendance were full of noise now and fittingly it was Invincibles captain Van Niekerk who hit the winnings runs, a thick edge flying beyond the wicket-keeper to earn victory with an unbeaten 56 off 42 balls.
It may be a very different format, but ultimately the team with the most runs still win with the hosts' 139 for five beating the Originals effort of 135 for six.