In the league, United are nine points clear at the top - albeit other sides around them have games in hand - putting Becky Langley's side in a strong position as they head into the campaign's final seven fixtures.
But Sunday's game gives them an opportunity to progress to the final of a national cup competition, which will be played at Luton's Kenilworth Road. However, opponents Pompey are also top of their league so it promises to be a hard-fought and entertaining affair.
This will be Newcastle United Women's fourth competitive outing at St. James' Park, with the team watched by crowds of 28,565 and 24,092 at the stadium last season after 22,134 attended their inaugural match there, against Alnwick Town Ladies in May 2022.
Newcastle also beat West Brom Women 3-0 in front of another big attendance at the stadium as part of the Sela Cup in pre-season.
Kick-off is at 14:00 GMT and matchday prices are £8 for adults and £2 concessions, with cash turnstiles in operation at the North West corner of St. James' Park.
But supporters who can't make the match will be able to watch for free on NUFC TV, while the game will also be streamed live on Newcastle United's official YouTube channel.
Commentary will come from BBC Newcastle's Matthew Raisbeck, who will be joined by former Lioness Aran Embleton, a Newcastle fan from Cramlington who became one of the first women from the North East to represent England and played in the Women's FA Cup final for Doncaster Belles in 2000, and United defender Jodie Bartle, who is nearing a return from a long-term injury.
Georgia Gibson has scored three goals in the previous three matches at St. James' Park and will be looking to add to that tally, while the ever-reliable Hannah Greenwood and in-form Paige Bailey-Gayle will be among the other players looking to catch the eye and inspire United to reach the final.
Can Langley's lasses book their place at Kenilworth Road and make it four wins out of four on the hallowed turf of St. James' Park? Watch live on NUFC TV or YouTube from 14:00 GMT on Sunday.