The 83-year-old former First Minister, who has represented North Antrim for 40 years, said that it was now time for a new generation of politicians to take over.
Mr Paisley was widely expected to retire as an MP after stepping down as DUP leader in 2008, but after the Traditional Unionist Voice took almost 70,000 votes from the DUP at last year's European election, he had signalled he might seek re-election.
The DUP will officially select its Westminster candidate for the North Antrim seat next week. Mr Paisley’s departure is likely to pave the way for a bitter personal battle between his son, Ian Paisley Jnr, and Traditional Unionist Voice leader Jim Allister.
His decision to stand down was announced in an interview with his local newspaper the Ballymena Guardian in which Mr Paisley claimed the DUP could retain the seat.
“I have no doubt that the people of North Antrim will again support the DUP candidate at the next election,” he said.
He has held the seat in North Antrim since 1970 and in his last general election in 2005 polled 25,156 votes giving him a crushing majority of almost 18,000 and increasing his vote by 4.8%.
“I fought in the 1970 campaign against the sitting Official Unionist MP Henry Clark. He had produced a picture of me at a public meeting in Kells and proceeded to set it on fire,” he told the Ballymena Guardian.
“The outcome of the election that followed got me into the Guinness Book of Records for the largest ever overturning of a majority.”
Famed for his firebrand oratory, Mr Paisley was a founding member of the Free Presbyterian Church in Ireland in 1951. His evangelical theology heavily influenced his political views and throughout the Troubles he forthrightly denounced Catholicism and the papacy.
During the conflict he was a fierce critic of power-sharing with nationalists and of the Republic having a say in Northern Ireland's affairs.
But in his later political life, the one-time cheer-leader for hardline unionism underwent somewhat of a political conversion which finally saw him enter office with his long-time enemy, Sinn Fein.
His decision to accept the position of First Minister alongside deputy First Minister and former IRA commander Martin McGuinness in 2007 saw him hailed as a peacemaker by moderates but criticised by many former followers who accused him of betraying Ulster.
What proved almost more remarkable was the warmth of the relationship the two erstwhile foes developed during their year in officer together, leading some to dub them the “Chuckle Brothers”.
In recent years Dr Paisley has been looking frail and suffered serious ill-health in 2004, later admitting that he had “walked in death's shadow”.
After leaving the Commons he joined his wife Eileen, who was made a Baroness in 2006, in the House of Lords.
His final years in the House of Commons have not been untouched by the expenses controversies that rocked British politics.
The ex-DUP leader was criticised for repeatedly claiming maximum £400-per month London food allowance payments, while double jobbing as Stormont's First Minister
Confirming his father’s intention to fully retire from politics Ian Paisley Jnr said his father had done a “fantastic” job and had “devoted his life” to the people of North Antrim.
Meanwhile political opponent Jim Allister said: “In the early years he did a very good job. We will will fight this election over every vote and will be honoured if the electorate vote us in.”