John Park said he is leaving to fight for workers" rights "at the coal face" as policy and strategy director of the Community trade union.
The Mid Scotland and Fife regional MSP, first elected in 2007, will be replaced by the next Labour candidate on the regional list, Jayne Baxter.
Mr Park, 39, co-ordinated Labour's unsuccessful election campaign last year. He formally notified the Presiding Officer of his pending departure and said: "Representing the people of Mid Scotland and Fife has been an enormous privilege and I am really grateful to have had that opportunity.
"I want to thank everyone who voted for me and Labour party members for the support they have given me. This is a decision that I have not made lightly and I now have the opportunity to represent thousands of workers across the UK.
"I've tried to use my time in politics to make sure the issues important to working people, jobs, apprenticeships and a living wage, are centre-stage.
"Now, as workers are under attack like never before, I am returning to my union roots to fight at the coal face.
"I wish Johann, who has been a good friend to me, and all my friends in the Labour group the very best for the referendum and upcoming elections. I am a strong Labour supporter who loves my country, so will be campaigning shoulder to shoulder with them in the months and years ahead.
"I would also like to thank Holyrood officials and my own staff who are undoubtedly the most dedicated group of people I have ever met. Their support and assistance has been invaluable."
Unlike constituency MSPs who are elected on a first-past-the-post system, regional MSPs are selected by the number of votes the party receives on the second ballot during Holyrood elections. Departing MSPs are subsequently replaced by a party member lower down the list.
Mr Park said: "I know Jayne Baxter and I've no doubt she will be a hardworking and diligent MSP."
The general secretary of Community, Michael Leahy, said: "I know this has been a difficult decision for John but I am delighted that he is returning to the trade union movement. His voice will be a powerful addition for our members.
"John's considerable experience of public life and getting things done will ensure that Community trade union are better equipped to represent working people in Scotland and right across the UK."
Johann Lamont said: “John will be a loss to the Scottish Parliament but I understand his reasons for stepping down and I know he will continue to play a significant role in the Labour movement.
“He has been a hard-working MSP for Mid Scotland and Fife, his home region, and has served the Labour group in a number of roles since he was elected in 2007 and I would like to thank him his for efforts.
“I wish him well in his new role and I look forward to campaigning with him in the run-up to the referendum and in future Scottish elections.”
In an article for the ScotsPolitics website in September, Mr Park accepted his part in losing the 2011 campaign but said lessons had since been learned.
He said there had been an unfounded perception created during the election that Labour "took Scotland for granted", but said the party had become stronger with Ms Lamont as leader and the new MSPs at Holyrood.
During the campaign he set out his plan to make 2011 a "doorstep election", attacking the SNP's slick advertising campaigns, but later conceded that Labour didn't make enough use of modern communication technology such as social networking.
He also sought to portray the SNP as "natural allies" of the Conservatives during the election, highlighting their joint-voting record, but in his post-election analysis he suggested it was misguided to focus on the Tories as they had once enjoyed a majority in Scotland which Labour has never had.
Mr Park has been an active trade unionist since leaving school at 15 to become an apprentice electrical fitter at Rosyth Dockyard in 1989 .
Within two years he was appointed trade union convener at Rosyth, before going on to work as a research officer and then national industrial campaigns officer at the Amicus union.
He was appointed head of employee relations at Babcock Naval Services in 2003, and then Assistant Secretary of the Scottish Trades Union Congress before becoming an MSP in 2007.
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