The game should have been played a couple of weeks ago but was postponed due to a waterlogged pitch.
Argyle beat Southampton 7-1 at home and drew 2-2 away to clinch promotion last season and they know that this could prove to be a tricky tie.
Southampton are riding high in South West Division One having won all their six league games to date.
However, they will be smarting after going down 2-1 to Marine Academy Plymouth in the FA Cup and will not want to lose to another team from the city.
The winners of this weekend’s tie will host Crawley Wasps in the third round on Sunday, December, 9
Argyle are still without top striker Natasha Knapman, who is likely to be out of action until the new year, while Becky Wakley is a doubt due to an ankle injury.
But there will be a welcome return from injury for Helen Bleazard, who will probably revert to her strike role, with Jessica Jones returning to the midfield.
Also returning to the squad is flying winger Amber Pollock after missing the last two games due to holiday and work commitments.
The management team of Dave Leonard and Trevor Rodd have also included development youngster Tamsin Medd-Gill in the squad.
Leonard (pictured above) said: “It’s another cup match and a team we will not be taking lightly as they were big rivals last season. We will give them every respect.
“We have been on a good run in the league and it will be a good test for the squad, everyone wants a cup run.”
Argyle squad: Lindsay Rogers, Mollie Taylor, Darcy Hepworth, Ebony Dover, Katie Middleton, Steph Beck, Jessica Jones, Kayley Lane, Becky Dandridge. Faye Ivall, Zoe Cunningham, Becky Wakley, Helen Bleazard, Amber Pollock, Tamsin Medd-Gill
After a break last week, Argyle’s development side will return to league action against Exeter & Tedburn at the Salt Mill (2pm).
They hope to carry on the form that they showed in the second half against Bideford a fortnight ago.
Their injury list has remained the same and they will also have to do without the services of Hannah Brock and player-coach Vicki Fannon. But they include Panagiota Papaioannou before she departs on international duty for Greece and they welcome back youngsters Nicola Champion and Kiara Robins.
Development Squad: Amy Darnley, Panagiota Papaioannou,Becky Parkyn, Rachel Javan, Jodie Randall, Kelly Vinnicombe, Alex Hugh, Sally Salter, Shania Fenlon, Gabi Alphous, Nicola Champion, Kiara Robins, Maya Ridge.