Theresa Villiers accused Mr Major and Tony Blair of being "irresponsible" with their claims
Former British prime minister John Major has warned that Brexit could "tear apart the UK" and trigger instability in Northern Ireland.
Speaking alongside Tony Blair in Northern Ireland, Mr Major said it would be a "historic mistake" to do anything that would undermine the peace settlement.
In a significant moment in the campaign, with the two old adversaries alongside each other, the former Conservative prime minister said relations had never been better and he worried about a British exit that would "leave Ireland on the other side of the table" in negotiations between Britain and the European Union.
He added that if the UK voted to leave it would have a huge impact on the economies of both Ireland and Northern Ireland.
Speaking to students at Ulster University, Mr Major made an impassioned plea to young people to stay in the EU, saying: "Europe is not for the elites, it is for you, for your generation ... We're not going to be around."
He said that in 1973 the UK was called the "sick man of Europe" and was now on track to be the biggest economy on the continent because of its membership of the EU.
He added that ordinary people had benefited from this.
Mr Blair said Europe was an "important part of the context" in which the UK was able to broker peace in Northern Ireland and that people there faced a "seismic decision" on 23 June.
The former UK Labour leader said that people advocating Leave did so in broad terms but when the detail was pointed out they "waved them away".
Mr Blair claimed the problems of reinstalling hard borders between the UK and Ireland were "immense" and would have a huge impact on people's daily lives and on relations between Northern Ireland and Ireland.
He said Leave faced "fundamental questions" about the common travel area that the people of Northern Ireland needed to see answered before the referendum.
And he accused them of "ignoring" Northern Ireland in the debate about leaving the EU.
Northern Ireland Secretary and 'Out' campaigner Theresa Villiers accused the former prime ministers of being "irresponsible" with their claims.
She said: "Support for the peace process in Northern Ireland is rock solid. The vast majority of people in Northern Ireland believe their future should only ever be determined by democracy and consent and not by violence.
"I very much hope figures who played such an important role in the peace process would not suggest that a Brexit vote would weaken that resolve in any way.
"Whatever the result of the referendum, Northern Ireland is not going back to the troubles of its past and to suggest otherwise would be highly irresponsible."
She said the common travel area would continue if there was a Leave win, even though the border would become the frontier between an EU member and a non-EU nation.
A poll for the Belfast Telegraph suggests that Northern Ireland would vote to Remain in the EU - with 56% opting for 'In' and 35% to Leave.