On January 20, 1942, a meeting is held in order to determine the method by which the Nazi government is to implement Adolf Hitler's policy, that the German sphere of influence should be free of Jews, including those in the occupied territories of Poland, Latvia, Estonia, Czechoslovakia and France. As the film opens, various officials from different German agencies arrive and mingle at a lakeside villa in the Berlin borough of Wannsee. Among those present:
- Wilhelm Stuckart (Colin Firth), a lawyer representing the Interior Ministry and co-author of the anti-Semitic Nuremberg Laws
- Friedrich Wilhelm Kritzinger (David Threlfall), deputy head of the Reich Chancellery
- Gerhard Klopfer (Ian McNeice), a Falstaffian lawyer from the Nazi Party Chancellery
- Otto Hofmann (Nicholas Woodeson), Chief of the SS Race and Settlement Main Office
- Martin Luther (Kevin McNally), the obsequious Foreign Ministry's liaison to the SS.
- Heinrich Müller (Brendan Coyle), Gestapo chief and Adolf Eichmann's immediate superior
- Josef Bühler (Ben Daniels), State Secretary for the General Government of occupied Poland
- Rudolf Lange (Barnaby Kay), a Sicherheitsdienst (SD) Commander
- Alfred Meyer (Brian Pettifer), Deputy Reich Minister, Reich Ministry for the Occupied Eastern Territories
- Erich Neumann (Jonathan Coy), the apparently out-ranked Director of the Office of the Four Year Plan
- Reinhard Heydrich (Kenneth Branagh), Heinrich Himmler's right-hand man in the SS, who begins by explaining the purpose of the meeting.
It is quickly established by those present that there is a significant "Jewish problem", in that the Jews of Europe cannot be efficiently contained, nor can they be forced onto other countries. Kritzinger interrupts at several points to opine that the meeting is pointless, given that the Jewish Question had previously been settled, but Heydrich promises to revisit his concerns.
A discussion follows of the possibilities of sterilization, and of the exemptions for mixed race Jews who have one or more non-Jewish grandparents. At this point, Stuckart loses his temper and insists that a sturdy legal framework is paramount, and that ad hoc application of standards will lead to administrative chaos. He also chides Klopfer for his simplistic portrayal of Jews as subhuman beasts, simultaneously painting his own picture of Jews as clever, manipulative, and untrustworthy.
Heydrich calls a break in the proceedings, and after praising Stuckart aloud takes him aside to warn him about the consequences of his stubbornness, implying that others in the SS will take an unwanted interest in his actions. When the meeting reconvenes, Heydrich steers the discussion in the direction of wholesale extermination using gas chambers. This causes consternation among some attendees, notably Kritzinger, who objects on the grounds that Hitler had given him personal guarantees that extermination of the Jews was not being considered, and Bühler who is shocked to discover that the SS have been building extermination camps and making preparations for the "Final Solution" under his nose.
It eventually become clear to everyone at the meeting that they have been called together not to discuss the problem but to be given orders by the SS, who are intent on wresting control of the operation from other agencies such as the Interior Ministry and the Reich Chancellery. Eichmann now describes the method that will be used, i.e. the gassing of Jews. Many have already been killed in specially-designed trucks and his figures include tens of thousands of victims. He even describes their bodies as coming out "pink" (a symptom of carbon monoxide poisoning), at which point Hofmann is suddenly taken ill. He later puts it down to a bad cigar.
Throughout the meeting and over refreshments attendees raise other side issues, reflecting the interests of their respective work areas. Lange warns executing Jews by shooting has a deleterious effect on the morale of his troops, and he clashes with Luther's indifference. Klopfer requests that the Party retains some discretionary power over the process. Bühler presses for urgency, concerned that typhus could break out from the over-populated ghettos in Poland. Meyer and Neumann do not want production stymied due to disruption or the loss of skilled workers. Heydrich admonishes Hofmann over his insistence that his office takes the lead in managing resettlement in Hungary.
A break is called and this time it is Kritzinger's turn to be taken aside and intimidated by Heydrich, who warns that Kritzinger is influential but not invulnerable. Heydrich tells Kritzinger that he wants not only consent but active support, and Kritzinger realizes that any hopes he had of assuring livable conditions for the Jewish population are unrealistic. In return, he tells Heydrich a cautionary tale about a man consumed by hatred of his father, so much so that his life loses its meaning once his father dies; Heydrich later interprets this as a warning that a similar fate awaits them if they allow their lives to revolve around antisemitism.
Heydrich then recalls and concludes the meeting, giving clear directives that the SS are to be obeyed in all matters relating to the elimination of the Jews. He also asks for explicit assent and support from each official, one by one. After giving careful instructions on the secrecy of the minutes and notes of the meeting, they are adjourned and begin to depart.
As the servants at the villa tidy away the remains of the meeting, and the officials depart, a brief account of the fate of each one is given. The movie ends with the house tidied up and all records of the meeting destroyed as if it had never happened. The final card before the credits reveals that Luther's copy of the Wannsee minutes, found by the United States Army in the archives of the German Foreign Office in 1947, was the only record of the conference to survive.