Moore, 39, cited the health of his young son Spencer as the reason for his leaving federal politics, but his departure was immediately pounced on by critics as more evidence the Conservatives are losing steam.
Moore is the latest in a string of long-time Tory MPs bowing out of this campaign. He's also among the longest-serving Tories from British Columbia, a province considered very much in electoral flux.
"Balancing family responsibilities while in public life is always a challenge," he said in a statement.
"This is particularly true when you have a child with special needs."
Moore married Courtney Payne, a former adviser in the prime minister's office, in 2011 and they have a son, Spencer, who has a form of skeletal dysplasia that requires extensive care.
The popular, fluently bilingual cabinet minister was first elected in 2000 and was among the earliest backers of Stephen Harper's bid for leadership of the Canadian Alliance and later Conservative parties.
Moore himself has long been rumoured to have leadership aspirations and even among Harper's inner circle is consider a potential successor to the prime minister.
He has not ruled out a return to politics, but he spent weeks mulling over his immediate political future and discussed it at length with Harper.
Moore's decision was cemented following a recent update to his son's prognosis.
"We fully understand his need to spend more time with his family and wish the minister, his wife Courtney and his son Spencer well," the Prime Minister's Office said in a statement thanking Moore for his service.
His departure strips the Conservative cabinet of one of its policy and political heavyweights. Moore was a popular draw at fundraising events for MPs from across the country and central to election strategy, especially in British Columbia.
The main fight there is expected to be between the New Democrats and the Conservatives and recent polls suggest Tory support is softening.
Conservative insiders estimate about 12 seats are in play, while the NDP put it closer to 15.
Moore won his urban Lower Mainland riding in the 2011 campaign with 56 per cent of the vote, with the New Democrats in second place with 30 per cent.
The NDP candidate this time around is former journalist Sara Norman. It was in a scrum with Norman in 2013 when Moore made a controversial comment about the role of the government in eradicating child poverty.
"Is it my job to feed my neighbour's child? I don't think so,” he said.
He later apologized.
It was a rare misstep for a minister widely respected in Ottawa and in the business community.
"The departure of @JamesMoore_org is a loss to Canadian politics," Perrin Beatty, president of the Canadian Chamber of Commerce, wrote on Twitter.
Moore was only 24 when he was first elected and has always been one of the more moderate voices on the right of the political spectrum; in 2004, he was one of only a handful of Conservatives who voted in favour of same-sex marriage.
He became industry minister in 2013, responsible for updating copyright legislation, selling off Canada's shares in GM and managing the lucrative auctions for wireless spectrum.
Before that, he was the minister for Canadian Heritage, responsible for the 2010 Winter Olympics as well as the controversial revamp which turned the Canadian Museum of Civilization into the Canadian Museum of History.
He was handed that portfolio in 2008 at a sensitive time for the Conservative government — after an election in which the Conservatives saw their support in Quebec plummet because of comments Harper made about the arts community.
At Heritage, Moore was responsible for repairing that damage and for a time after the 2011 election, Ottawa insiders joked he was the de facto sixth Conservative MP from Quebec.
Moore's departure follows an announcement by Justice Minister Peter MacKay earlier this month that he would not run again. Earlier this week, popular Alberta Conservative MP, James Rajotte, also declared he was standing aside.
Altogether, 34 of the 166 people elected as Conservatives in 2011 aren't running again.