South Africans 304 for 8 (Van der Dussen 95, De Bruyn 88, Edwards 3-45) and 347 lead Cricket Australia XI 226 (Kellaway 105, Doran 78, Ngidi 3-26, Coetzee 3-36) by 425 runs
Van der Dussen was crestfallen to miss out on his century, having been run out after Temba Bavuma sent him back after he called for a single. The 33-year-old had missed the final Test of the recent England tour and the T20 World Cup with a broken finger.
De Bruyn, 30, played his last Test in 2019 and his positive knock may be the tonic to invigorate the next stage of his career.
Captain Dean Elgar, who top-scored with 109 in the first innings, said after play on the first day it was imperative South Africa made substantial totals in the coming Test series to give their strike pacemen the opportunity to put pressure on Australia's batters.
They breathed a sigh of relief when Test vice-captain Bavuma strode to the crease just before lunch. Bavuma, who made 28, didn't bat in the first innings after reinjuring an elbow that had kept him out of the recent Test tour of England.
He wore a compression bandage on his left arm when he batted. His recovery is a huge boost to South Africa's chances in the first Test against Australia at the Gabba starting on December 17.
Van der Dussen was in supreme form. His drives down the ground were crisp and effective and he played a suite of reverse sweeps to the boundary off spinner Matt Kuhnemann.
Bavuma faced a much-needed 92 deliveries and showcased his strength square of the wicket, which is paramount for batters on Australian pitches.
De Bruyn was pleased with his own knock and impressed with Bavuma's return from injury ahead of the Tests.
"If you look at his career he is one of those characters that really stand out when the team is under pressure," de Bruyn said. "He looked really calm today and...that is something for him to take into next week.
"Our team has played well. We've set the game up nicely. Usually I am batting earlier and you have to break down the bowlers but today I came in and they were tired so it was quite nice to bat."
The accomplished 80 made by wicketkeeper Kyle Verreynne in the first innings was another positive just six days from the first Test.