The story is set in the year 2021, three years after the threat of GUILT had been eradicated and seven years prior the events of Trauma Center: New Blood. The Republic of Costigar in Africa is a country that has been plagued by warfare for over a decade, and is finally on the road to peace. However, they still struggle with attacks by guerrilla militants, land mines, and many refugees. Despite this, the country is slowly on its way to becoming a peaceful nation. Countries around the world have been sending aid to the country, as well as building hospitals to help the people. However, they are very short on staff and need more to be able to take care of all of the patients.
Doctor Derek Stiles, along with his faithful nurse Angie Thompson, travel to Africa to one of the refugee camps called Zakara. When the game begins, they have been working there for several months, both to help patients and investigate a new fever.
Reception of Under the Knife 2 has been generally positive, with an 82% on Metacritic and an 84% on GameRankings. Many praised the surgical gameplay and graphics, while the biggest weak spot was that Trauma Center got too familiar for some. NintendoWorldReport gave Under the Knife 2 the most negative score.