The Scottish Lib Dem leader scored a 7,448 vote advantage over the SNP's Rhuaraidh Fleming, up from his lead of 3,465 in 2016.
Mr Rennie said he was "quite humbled" by the resounding victory.
"I was brought up in North East Fife, in Strathmiglo and went to school in Cupar, so it's a real honour to be elected with such a majority," he said.
"It's a big responsibility. I need to make sure I stand up for people in North East Fife, be the voice in parliament as well as deliver all the things I said on the election platform.
"It's a big honour but a big responsibility."
While the SNP's Rhuaraidh Fleming failed to break ground against the seasoned Lib Dem, the Nationalist party picked up an additional 3,000 votes over their 2016 total - suggesting a surge in support for the party and its agenda to deliver a second independence referendum.
However, Mr Rennie is upbeat about his party's own chances as constituency and regional results come out over the next 24 hours.
"Nicola Sturgeon herself acknowledged during the election campaign that the referendum is being pushed back," he continued.
"The mandate that she receives, whatever it is, is not as clear cut as perhaps she would like it to be.
"And we think it's pretty clear that people were saying very clearly that they do not want another referendum and want to focus on recovery."
He added: "I think we're going to do well tomorrow. It's difficult to tell how exactly it will play out but I'm confident we can gain more seats over the next couple of days - and if it's anything like North East Fife we're going to do very well."
Mr Fleming, meanwhile, has seized upon his party's increased vote count as a sign of rising support for independence in North East Fife.
Posting on Twitter, the SNP candidate said: "The highest ever number of votes recorded by an SNP candidate in this constituency showing we worked our socks off and gained thousands of new supporters.
"On the regional vote we outpolled every party clearly showing that support for @theSNP is higher than it has ever been here. I fought a campaign standing *for* something.
"The SNP has had excellent results elsewhere and, on current results, will form the next Govt.
"With a pro-independence majority in the next parliament, as is possible based on results so far, it will be unthinkable for any true democrat to deny the people of Scotland a choice on their own future, post-Covid.
"In North East Fife, this is a good result for @theSNP, just not the one we wanted or worked for."
Turnout was 67.81%, up 4.64 percentage points on 2016, with 59,596 people registered to vote, a quarter of whom registered to vote by post.
Willie Rennie (LD) 22,163Rhuaraidh Fleming (SNP) 14,715Wendy Haynes (LAB) 1,056Rhona Metcalfe (CON) 2,323