Lowry delighted the thousands of fans following him around the Dunluce links in the first Open to be held in Northern Ireland since 1951, with an eight-under par round of 63 to seize the lead on Saturday.
His 16-under overall total of 197 is the lowest after 54 holes in British Open history.
However, Lowry's chances of beating the overall record to par of 19-under set by Tiger Woods at St. Andrews in 2000 could be undone by bad weather.
After glorious conditions that allowed Lowry to go low on Saturday, heavy rain and strong winds are expected to return so his tee time has been moved forward to 1247 GMT.
The first raindrops started to fall in the morning, with the wind picking up to almost 20 mph.
"I know tomorrow is going to be a difficult day. I know there's some bad weather coming in, but I'm in a good position," said Lowry, who will be roared on by the home fans as he bids to become the first golfer from either the Republic of Ireland or Northern Ireland to win a major since Rory McIlroy in 2014.
"I just have to do what I've been doing all year and hit the reset button tonight and go out there and shoot as good a score as I can tomorrow."
Fleetwood is also looking for his first major after a starring role in Europe's Ryder Cup victory last year.
The world number 20 was in fine form on Saturday with a bogey-free round of five-under.
"I'm looking forward to it," said Fleetwood of his final-round showdown with Lowry.
"It's going to be another chapter in my career, no matter what happens and it's going to be a very special day."
Fleetwood has a two-shot advantage over J.B. Holmes on 10-under, but a host of the world's best players are poised to make their move should the leaders falter.
World number one Brooks Koepka has not failed to finish in the top two in all three majors so far this season and will tee off in the penultimate group with Holmes after two birdies in his final two holes on Saturday took him to nine-under.
And Koepka is hoping Lowry and Fleetwood are blown off track.
"Thankfully it's going to blow tomorrow," said the four-time major champion.
"Here you need some wind, you need some rain. You need anything that can kind of go your way. And that's got to be an advantage."
World number three Justin Rose, who finished tied for second at last year's Open, is also on nine under.
Two of the most talented players on tour never to have won a major, Lee Westwood and Rickie Fowler, tee off at eight-under.
Jordan Spieth, Open champion two years ago, Jon Rahm, Danny Willett and Tony Finau also form a dangerous group at seven-under with the potential to shoot themselves into contention.