The story is set in 19th century Russia. Anna Karenina (Greta Garbo) is married to a wealthy government official, Karenin (Basil Rathbone), and has a young son, Sergei (Freddie Bartholomew). She visits her brother, Stiva (Reginald Owen), to help resolve his marriage issues caused by his infidelities. While there, she meets Count Vronsky (Fredric March) and they fall deeply in love with each other. When she returns home, Anna continues to see Vronsky despite her marriage. She asks Karenin for a divorce, but he refuses and warns her that if she becomes Vronsky's mistress, she will lose all claim to their son. In spite of this, Anna, driven by her love for Vronsky, chooses to be with him.
Initially, their life together is idyllic, but Vronsky begins to miss the military life and after a fight with Anna, he re-joins the army. Anna goes to the train station to reconcile with him and sees him being introduced to a girl by his mother (May Robson). In that moment she realizes that she has lost everything that was important to her and tragically throws herself in front of a train.