The Northern Ireland Secretary says she will vote to leave the EU "to take back control over our country and making our laws and controlling our borders".
Theresa Villiers said there were "risks on both sides of this debate" but the "safer option" was to leave.
Ms Villiers said the UK could then "negotiate a new deal based on free trade and co-operation".
So far, she is one of five full members of the cabinet in favour of leaving the EU, with 16 supporting staying.
Others who have joined the Leave campaign are Michael Gove, Chris Grayling, Iain Duncan Smith and John Whittingdale.
Mr Cameron has warned that leaving the European Union would be a "leap in the dark", as he urged voters to back his reform deal.
The PM said: "Those who want to leave Europe cannot tell you if British businesses would be able to access Europe's free trade single market, or if working people's jobs are safe, or how much prices would rise.
"All they're offering is a risk at a time of uncertainty - a leap in the dark."
'Optimistic about UK'
Ms Villiers, who was an MEP for six years, said she did not think the EU system was "capable of changing in a way that would be the right option for us".
She said: "In the decades ahead we face a European project that is ever more determined to integrate, to take more powers and we could be outvoted many times over the years to come.
"So there is no stable status quo for us to cling to.
"Even with this deal [negotiated with EU leaders by David Cameron] we will still be subject to the Court of European Justice who may still do its best to unpick the deal that's been agreed."
Ms Villiers said she was "profoundly optimistic" about the UK, which she said could "flourish outside the EU".
She said Mr Cameron had won "important concessions" in Brussels.
"But the reality is a really radical way to change our relationship is to vote to leave and then negotiate a deal based on the trade and co-operation that people thought we were signing up to when we joined the European Union.
"It's long overdue that people have a right to decide on this, David Cameron is delivering that."
Ms Villiers said there had been "a sense of history" at Saturday's cabinet meeting at which ministers discussed which way they would vote in the referendum in June.
"It was quite emotional. It was also very measured, very objective, very sincere," she said.
"There was a determination that we wanted it to be a high-quality debate so people can make an informed choice, and to work courteously with each other even if we find ourselves on different sides."
She said it was "very difficult to be on a different side" to Mr Cameron but she didn't believe the divisions in the cabinet would lead to civil war in the Conservative Party.
"Ultimately, [it is] the arguments about what is good for our future, what will generate the best prosperity, what will make us most secure that will determine how people vote in the referendum - not how each cabinet member will vote."
The Republic of Ireland's main opposition party criticised Ms Villiers' decision, saying it was "wrong for Northern Ireland" and "deeply worrying".
Fianna Fail spokesman on foreign affairs Brendan Smith said: "Secretary Villiers is entitled to her own views on this matter and that must be fully respected.
"However, I believe it is clear that a Brexit would be bad for Northern Ireland and bad for Irish-British relations."