Warner's innings was also more runs in one innings than any other Australian managed for the whole series - a campaign which is now the worst two-nation one-day result in Australia's history.
Defeat means captain Steve Smith has now lost nine of his past 11 matches in charge of the national team.
After the hosts chose to bat first, Australia began the match brightly with Joe Mennie quickly erasing memories of his horror debut in Johannesburg a week and a half ago.
Mennie - who conceded the worst figures by an Australia on ODI debut in game two of the series - dismissed both Hashim Amla (25) and captain Faf du Plessis (11) in a five-over opening spell that also included two maidens.
That burst reduced the hosts to 3-52 but Rossouw and JP Duminy (73) combined in a 178-run fourth-wicket stand to lift the South Africans back into control.
Roussow, who had earlier scored two half-centuries in the opening two matches of the series, finished with 122 to end the series with 311 runs at 77.75.
Mennie was the pick of Australia's bowlers, taking 3-49 off 10 overs while fellow newcomer Chris Tremain also finished his tour well with career-best figures of 3-64.In reply, Australia began well with Warner and Aaron Finch (19) adding 72 for the first wicket.
Imran Tahir (2-42) then bowled both Finch and Smith (0) as he opened his evening with a double-wicket maiden.
Impressive South African youngster Adile Phehlukwayo (1-51) dismissed George Bailey (2) as Australia lost three wickets for just three runs.
Warner combined with Mitch Marsh (35) and Travis Head (35) to keep Australia in the hunt but the opener simply ran out of partners as he tried valiantly to end Australia's dismal tour on a high.
The two teams will now meet in a three-Test series starting in Perth on November 3.
MOST LOSSES BY AUSTRALIA IN A BILATERAL ODI SERIES
5 v South Africa (A) in 2016 (SA lead 5-0, one to play)
4 v South Africa (A) in 1994 (Series drawn 4-4)
4 v West Indies (A) in 1995 (Windies won 4-1)
4 v South Africa (H) in 2009 (SA won 4-1)
4 v England (A) in 2012 (Eng won 4-0)