Prentice was appointed Minister of Industry on August 14, 2007, and after the 2008 election became Minister of Environment on October 30, 2008.
On November 4, 2010, Prentice announced his resignation from cabinet and as MP for Calgary Centre-North.
After retiring from federal politics he entered the private sector as vice-chairman of CIBC.
Prentice entered provincial politics in his home province of Alberta, and ran for the leadership of the Progressive Conservative Association of Alberta to replace Dave Hancock, who was serving as interim Premier and party leader after Alison Redford's resignation.
On September 6, 2014, Prentice won the leadership election, becoming both the leader of the Progressive Conservatives and as such the Premier, as his party held a majority in the Legislative Assembly of Alberta.
As Premier of Alberta, Prentice formed a new cabinet consisting of some members from the previous government, but also new Ministers including two who did not hold seats in the Legislature—Stephen Mandel and Gordon Dirks.
All three stood as candidates in by-elections scheduled for October 27, 2014, and all three were elected with Prentice becoming the MLA for Calgary-Foothills.
After introducing his first budget in 2015, Prentice declared an early provincial election on May 5, 2015, "bypassing" Alberta's fixed election date laws.
In the election, Prentice's PCs were defeated, dropping to third place in the legislature with 10 seats – ending 44 years of Tory rule in Alberta, the longest unbroken run in office at the provincial level in Canada.
Despite winning re-election in Calgary-Foothills, on election night Prentice resigned as both PC leader and MLA and retired from politics after results indicated that the Alberta NDP had won a majority government.On October 13, 2016, Prentice and three others were killed when the aircraft in which they were travelling crashed shortly after taking off from Kelowna, British Columbia.
The flight was en route from Kelowna to Springbank Airport, just outside Calgary.