Former Labour leader Mr Miliband and ex-Conservative chief Iain Duncan Smith will both guest host the topical debate show for five days each.
Head of Radio Two Lewis Carrie said: "I am delighted that Ed Miliband and Iain Duncan Smith will be presenting the Jeremy Vine Show.
"Both have held crucial roles in political life and will bring unique perspectives and insight to the programme."
For five days each in the weeks beginning 19 and 26 June from midday - 2pm, Ed and Iain will front the programme, which attracts a weekly audience of 7.07m.
Ed will host the show the week commencing 19 June and Iain the week commencing 26 June.
Editor of the Jeremy Vine Show Phil Jones said: “This follows a tradition of Radio 2’s popular current affairs show, being occasionally guest-presented by prominent politicians which began with figures such as Neil Kinnock and the late Charles Kennedy in the early 1990s.
"Political coverage is the bedrock of the programme and this is a sign of how important politics is to Radio 2, especially at such a key time in the nation’s history. Each day we will cover the big stories that affect our listeners and continue to inform, educate and entertain the Radio 2 audience.”
The show intersperses interviews and topical debate with phone ins, music and regular guests.