In the first round, the amateur (with Negreanu at their side, acting as their coach and lending advice) must defeat a celebrity such as Jayde Nicole, Jerome Bettis, Joanna Krupa, John Salley or Tito Ortiz.

In the second round, the amateur (with Negreanu now helping them from a sound proof booth, giving them advice through a listening device in the amateur's ear) must defeat a professional poker player such as Vanessa Rousso, Barry Greenstein, Joe Cada or Chris Moneymaker.

In the first episode that aired on October 11, contestant Father Andrew Trapp defeated John Salley, Rousso and Negreanu, winning $100,000 and a trip to the Bahamas in the process, all of which he promised to donate to his church in Garden City, South Carolina.

[9][10] On the November 22 episode after contestant Oluwasegun Odumuyiwa lost to Bettis, Brian Barboza defeated Nicole, Rousso and Negreanu, winning $100,000 and a trip to the Bahamas.

[11] In December Joanna Krupa and Joe Cada were announced as newly added as celebrity and professional opponents.

Dwayne Buth, playing on behalf of the Cal State Fullerton wrestling team, lost to Ortiz.

[5] Professional poker player Doyle Brunson has been critical of both Million Dollar Challenge and its contemporary rival Face the Ace as terrible shows unlikely to draw viewers.

[16] Negreanu responded, via blog, to this type of criticism that the show is not intended for the serious poker player, but rather is aimed at more casual audience.