Following the election of Tom Elliott as UUP leader, McCallister was appointed the Party's deputy leader. The following year the UUP WhipFred Cobain lost his seat in the Assembly and McCallister was chosen to replace him. After attending a Sinn Féin conference in November 2011 in Newry he issued an apology for "unionist failings" in the past. Families Acting for Innocent Relatives leader and prominent unionist activist Willie Frazer stated that people in the unionist community were "appalled" by McCallister's remarks. In March 2012 he performed an emergency delivery of a baby on his wife when they were unable to reach the hospital on time. He has stated the importance of his party reaching out to Catholic voters. In contrast with some previous Unionist leaders he would happily support his local GAA team and would have no opposition to Gay Pride marches. After being called the "leader of the opposition" by culture minister Carál Ní Chuilín, McCallister said, "If I win the leadership I think that title could quickly catch on. It has a ring to it."
UUP leadership election of March 2012
McCallister fought the UUP leadership in March 2012 losing to Mike Nesbitt by 129 votes to 536. McCallister was sacked by Mike Nesbitt as UUP deputy leader on 1 October 2012 for making a speech criticising unionist unity, which was seen by Nesbitt as an attack on his leadership.
Resignation from the UUP and NI21
On 14 February 2013, McCallister announced that he had resigned from the UUP in reaction to the decision to field a unionist unity candidate in the Mid-Ulster by-election. He declared that he would sit as an Independent Unionist in the Assembly. In an interview the following day Basil McCrea, who had also resigned from the UUP, suggested that he and McCallister were preparing to launch a new moderate unionist party. The new party, NI21 was launched in June 2013. McCallister became deputy leader with McCrea as leader. Two days before the 2014 European and local elections in which the party performed poorly, NI21 announced it would be changing from Designated Unionist to Designated Other in the Northern Ireland Assembly. McCallister criticised the move, which he labelled "crazy" and evidence of how "dysfunctional" NI21 had become. McCallister alleged the decision had been made without proper consultation McCrea then demanded an explanation from McCallister for his comments and stated the executive would discuss the comments. In July 2014 amid allegations of inappropriate behaviour by McCrea, McCallister resigned to resume sitting in the Northern Ireland Assembly as an independent. He lost his seat in the 2016 election.
Fraud allegations
In June 2015 the Police Service of Northern Ireland raided McCallister's home over allegations relating to the misuse of public funds A number of items including a computer were seized and police referred the case to the Public Prosecution Service.