Karpani's milestone will come when she is substituted on in Friday's WXV Global Series clash against Scotland at GIO Stadium in Canberra.
The Wallaroos mainstay missed her side's victory in Edinburgh last month with a back injury and returned off the bench in Sydney against the tourists on Saturday.
She iced the Wallaroos' 56-12 thrashing with a rampaging try, dragging three defenders over the line on the siren.
Karpani reflected on her career when the team line-up was announced on Thursday for the final face-off against the Scots.
"I take a lot of pride in it, and so do the girls beside me in this team, and within the wider squad," she said after taking a moment to wipe back tears.
"It's super important to also recognise where we've come from and where we are now. When I first came through the Wallaroos program, we had two Test matches a year, sometimes four."
The 30-year-old also endured the COVID-19 years when games weren't played, but will become the second Wallaroo to join the half-century club, alongside Michaela Leonard.
"Fifty tests in the women's space is an incredible milestone," Wallaroos assistant coach Mike Ruthven said.
"For her to be able to do that in the front row as well, is a credit to her."
However, it's not the only celebration taking place on Friday.
It will be Emily Chancellor's final game for the Wallaroos after she announced her retirement earlier in the week.
Then, hours after Wednesday's news conference, Cecilia Smith announced she too will be stepping away from international rugby after the match.
"I'm just a country girl from Leeton who decided to give footy a crack after having my little girl," the Samoan-born 32-year-old said in a statement.
"Somehow I ended up here representing Australia".
She will finish her career with 34 caps, while Chancellor will finish with 42.
"(Smith) hanging up the boots was also quite emotional," Karpani said.
"Two girls in the one campaign was really tough to pill to swallow, especially two really inspirational women".
Desiree Miller, who scored two tries in a sharp display at fullback in Sydney, will miss Friday's Test to manage calf soreness.
Faitala Moleka will move from the centres to cover Miller, while Cecilia Smith will wear the No.12 and Ella Ryan is added to the bench.
Australia snapped a six-game losing streak with their Edinburgh win against Scotland, who are yet to beat the Wallaroos.
WALLAROOS SQUAD: Allana Sikimeti, Tania Naden, Faliki Pohiva, Kaitlan Leaney, Tiarah Minns, Siokapesi Palu Sekona (capt), Emily Chancellor, Piper Duck, Samantha Wood, Waiaria Ellis, Amelia Whitaker, Cecilia Smith, Georgina Friedrichs, Maya Stewart, Faitala Moleka. Bench: Brittany Merlo, Brianna Hoy, Eva Karpani, Michaela Leonard, Pia Tapsell, Lily Bone, Piper Simons, Ella Ryan.
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