Mandhana, who has scored 167 runs in seven innings, will be replaced by Ireland’s Gaby Lewis.
Harmanpreet Kaur will also fly home after missing Manchester Originals’ last two games with a quad injury.
“It’s been a fantastic competition and I’ve really enjoyed it,” said Mandhana.
“I would love to be able to stay with the team until the final but we’ve been away from home for a long time with more tours ahead. I’ll be watching the team at Lord’s and hoping they can continue our good form.”
Opener Lewis, who made her Ireland debut as a 13-year-old in 2014, becomes the second Irish player to join Southern Brave after Paul Stirling signed for the men’s team last month.
“It’s a very exciting opportunity, and I can’t wait to get over there,” said the 20-year-old Dubliner.
“It’s a great chance to be around, and learn from, some of the best in the world, and I want to thank the Southern Brave for giving me the opportunity.”
Brave qualified for the 21 August final at Lord’s with a 39-run win over Welsh Fire on Wednesday, with Mandhana scoring 78, while Kaur’s Originals’ side are bottom of the eight-team table.
In the men’s competition, third-placed Trent Rockets have recalled Marchant de Lange, who took eight wickets in four games earlier in the tournament, to replace the injured Wahab Riaz.
Source: BBC Sport