Harwood-Bellis came on in the 62nd minute in place of Kyle Walker but did not wait long to make his mark.
The Southampton defender rose highest to get on the end of an inviting ball from Jude Bellingham at the back post and head it past a despairing Caoimhin Kelleher.
Harwood-Bellis' goal was England's fifth and final goal of their emphatic result over a ten-man Ireland that secured the Three Lions' return to League A in the Nations League.
Keane, who won 67 caps for Ireland during his glittering playing career, was keenly invested in Harwood-Bellis' performance given the Saints star is his future son-in-law.
Harwood-Bellis got engaged to Keane's daughter, Leah, earlier this year.
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So when the centre-back sent his header past Kelleher, it left Keane somewhat torn.
The Cork native also served up a hilarious response when asked what it meant for Harwood-Bellis and his daughter's future together.
"Bittersweet to me," Keane said when asked of his thoughts on Harwood-Bellis' goal.
When it was pointed out not everyone knew the relation between Harwood-Bellis and Keane, the Manchester United great said: "It's not done and dusted yet. Things can change quickly in the Keane household."
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Keane's remark left fellow pundit Ian Wright, and no doubt many viewers watching across the country, in stitches.
Although Keane did add that he should be able to get over Harwood-Bellis' goal, adding: "It's good for him to make his debut, he's a bit of a goal threat. He's a nice kid, his family have done a really great job. Really nice kid."
Harwood-Bellis and Keane will no doubt have a debrief after the game, as the former opened up on what it's like to be the future son-in-law of a footballing icon prior to the Greece fixture.
"It's something that is good, yes, and I take a lot of advice," Harwood-Bellis said.
Harwood-Bellis was one of eight stars handed their senior England debuts by interim boss Lee Carsley during his six-game stint in charge.
Morgan Rogers, Tino Livramento, Morgan Gibbs-White, Lewis Hall, Curtis Jones, Noni Madueke and Angel Gomes were all trusted to perform for the Three Lions by Carsley.
None of the fresh faces did anything to harm their chances of future England call-ups either as all eyes begin to turn towards the 2026 World Cup.
What is most notable about those handed their debut by Carsley is that they are all aged 24 or under.
According to Carsley, the main logic behind so many stars earning their first caps was to give incoming England boss Thomas Tuchel more options to choose from when the March international window arrives.
"What we have tried to do is increase the amount of players available to Thomas," Carsley said.
"It feels like the fans are really connected with the team. They like the fact that it looks younger, it looks energetic, it looks fresh."