Die zweite Staffel wird seit den 27. September auf CBS ausgestrahlt.
Season two explores the pursuit of the Machine by a variety of entities, each with its own objectives. The FBI continues its drive to capture "The Man in the Suit", while Reese, with Carter's assistance, attempts to evade detection. HR, decimated after the season one finale, breaks with Elias and begins to rebuild itself with the assistance of the Yogorov family. A new group, Decima Industries, appears under the guidance of former MI-6 agent, Greer. Plotlines include:
- Reese's search for Finch who was kidnapped by Root in the season one finale. As he does, Root's past slowly unravels in a series of flashbacks.
- Carter and Fusco, now both aware of Finch and Reese's activities, become increasingly important to their missions.
- Nicholas Donnelly's obsession with finding "The Man in the Suit," Reese's arrest and Carter's attempts to free him.
- Examination of Finch's partnership with Nathan Ingram, his relationship with Grace Hendricks, and the bombing that killed Ingram through a series of flashbacks.
- The collapse and rebuilding of HR under Alonzo Quinn and Patrick Simmons.
- The introduction of Decima Industries, including Kara Stanton's recruitment by Greer. Stanton uses Reese and Mark Snow to plant a the virus designed to take over the Machine.
- The exploration of how the Machine serves the Program (aka Northern Light), Special Counsel, Hersh and their activities, including the introduction of Sameen Shaw, a field operative in the Program.
- Jim Caviezel as John Reese (22/22)
- Michael Emerson as Harold Finch (22/22)
- Taraji P. Henson as Joss Carter (22/22)
- Kevin Chapman as Lionel Fusco (18/22)
- Jay O. Sanders as Special Counsel (8/22)
- Boris McGiver as Hersh (7/22)
- Amy Acker as Root (6/22)
- Robert John Burke as Patrick Simmons (6/22)
- Clarke Peters as Alonzo Quinn (6/22)
- Sterling K. Brown as Cal Beecher (6/22)
- Brett Cullen as Nathan Ingram (5/22)
- Brennan Brown as Nicholas Donnelly (5/22)
- Al Sapienza as Raymond Terney (5/22)
- Ken Leung as Leon Tao (4/22)
- Enrico Colantoni as Carl Elias (4/22)
- Carrie Preston as Grace Hendricks (4/22)
- Sarah Shahi as Sameen Shaw (4/22)
- Brendan Griffin as Charles Macavoy (3/22)
- Brian Hutchison as Brian Moss (3/22)
- Creighton James as Wayne Packer (3/22)
- Michael Kelly as Mark Snow (3/22)
- James Knight as Brian Kelly (3/22)
- John Nolan as Greer (3/22)
- Annie Parisse as Kara Stanton (3/22)
- Paige Turco as Zoe Morgan (3/22)
- Michael McGlone as Bill Szymanski (2/22)
- Cotter Smith as Denton Weeks (2/22)
- Morgan Spector as Peter Yogorov (2/22)
- David Valcin as Scarface (1/22)
- Anthony Mangano as Kane (1/22)
- Luke Kleintank as Caleb Phipps (1/22)