Flynn's side are 22nd in League Two, two points above Hartlepool in the final relegation place.
A win will ensure the Exiles remain in the EFL, but if Pools beat title-chasing Doncaster Rovers, they could return to the National League.
"If we win, it's going to be the biggest party in Newport for a long time," Flynn told BBC Radio Wales.
He continued: "I'm not going to pull any punches or dress it up, it is the biggest game [in their modern history] for so many reasons. It means so much to the club and amazing fans and to me."
Newport were beaten 2-1 by Carlisle United on Saturday after leading in the 12th minute in a game which could have wrapped up their EFL survival.
Flynn says the game against Notts County will be difficult to watch but believes his side can take the win they need to stay up.
"It's going to be horrendous, it's going to be nerve-wracking but I really think the boys are going to deliver because they've been brilliant and I can't ask for much more so I'm quietly confident but it will be a stressful time," he said.
"We've had some unbelievably tough games considering the league and position we were in but they've answered everything and every time we've lost, we've had a good response so I'm hoping we'll get one on Saturday."
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Newport County boss Mike Flynn says their game against Notts County is the biggest in the club's recent history.