Minister for Social Protection Heather Humphreys has said she gave her role as a TD her "absolute all" but added she is "getting older like everyone else".
Ms Humphreys said she decided to not stand in the upcoming general election after "careful consideration".
Speaking to RTÉ's This Week, the former deputy leader of Fine Gael said: "This is something I've thought long and hard about and the reason is very simple.
"I'll be 65 next year and if I ran again I'd be nearly 70 by the end of the next Dáil term and I'm just not physically able to keep going for that long.
"I was first elected to the Dáil on the 27th of February 2011 and from that day to this, I've given this job my absolute all, and of course, that's the only way you can do this job.
"It demands a lot. There's no work-life balance in politics. It's all-consuming now."
"I have to say I've enjoyed every minute of it, but the bottom line is I'm getting older and like everyone else," she added.
Ms Humphreys also ruled herself out of next year's presidential race saying it is "not on the cards for me".
She said she is not considering it for the same reason she decided not to run in the next general election.
"Unless I can give it 100%, I won't do it. I’ll keep working of course, to the best of my ability, for the remainder of the government term.
"When the next government is formed and the new cabinet is appointed, that will mark the end of my time in public life.
"I've been at it now for 21 years and I do believe it's time to take a step back.
"I have two beautiful little grandchildren, and I am looking forward to spending more time with them," she added.
Earlier, Ms Humphreys said: "Politicians are human too, we give all we can for as long as we can but time catches up on us all."
"I want to thank the people of Cavan and Monaghan for putting their trust in me and electing me to Dáil Éireann. It has been the greatest honour of my life to represent you," Ms Humphreys added.
Taoiseach Simon Harris paid tribute to Ms Humphreys and described her as a "trailblazer in Irish politics".
In a statement, he said: "She has been a reforming Minister for Social Protection introducing the long-talked about auto enrolment pension system and pay related social welfare to help people who lose their jobs. Her legacy will be ensuring every child has a hot meal during the school day.
"In Rural Affairs, she has overseen record investment in rural Ireland. There is not a county in Ireland that has not seen investment under the leadership of Heather.
"She has served in five Departments including as Minister for Justice, Arts and Enterprise.
"Anyone who knows Heather knows her entire political career has been driven by a sense of decency, fairness and compassion. She is a proud, mischievous Monaghan woman with a loud laugh and a heart of gold."
"She is a great friend and has been a loyal and dedicated Minister and Deputy Leader," Mr Harris added.
He also said Ms Humphreys will remain Minister for Social Protection and Rural Affairs.
Ms Humphreys said she informed the Taoiseach of her decision to step down at the end of August.
She said Mr Harris had asked her to reflect on it but understood her reasoning and wished her well.
She added that she had felt physically exhausted after campaigning for candidates running in this year's local and European elections and wanted to "slow down".
The announcement came as a surprise to many and it means that 18 of the 35 Fine Gael TDs elected in 2020 are leaving politics.
She was first elected in 2011 and she has been a member of the Cabinet for the last decade.
The Cavan-Monaghan TD was seen as favourite to top the poll in her constituency in the forthcoming election which is just weeks away.
Ms Humphreys is seen as a strong voice on rural issues in the Government and was regarded by many colleagues as one of the party's key electoral assets.
She is known for her common sense and straight talking approach to matters and was promoted to deputy party leader by Simon Harris earlier this year.
Those in her local constituency organisation said that her decision is based on a belief that she does not have the energy to commit to another five years in politics.
(Above: Cootehill residents react to Humphreys' decision not to stand in election)
McEntee appointed Fine Gael deputy leader
Minister for Justice Helen McEntee has been appointed deputy leader of Fine Gael following Ms Humphreys' announcement.
In a statement, Ms McEntee paid tribute to Ms Humphreys and said she "has given over 20 years of exemplary public service to her country, to the people of Monaghan and Cavan, and to the Fine Gael party".
Ms McEntee also thanked Taoiseach Simon Harris for "placing his trust" in her.
She said she looks forward to working with him "for our country and for our party".
"As Deputy Leader I will work every day with our Leader, with party members, councillors, candidates and the parliamentary party, to deliver from those core Fine Gael values policies and projects," Ms McEntee added.
Additional reporting Mícheál Lehane
