The show revolves around Gujarati homemaker Anupamaa, who is a devoted wife, mother and daughter-in-law. She has a family-oriented and self-sacrificing nature. Time and again, she is humiliated for being a mere housewife and for having an incomplete degree and education.

Anupamaa's husband, Vanraj Shah has been having an affair with his colleague, Kavya Gandhi for the past 8 years. Despite being warned by her best friend, Devika and Kavya's husband, Aniruddh, she refuses to believe it and expresses her faith in Vanraj. On her 25th Wedding Anniversary, when Anupamaa sees Vanraj and Kavya getting intimate, she is left shattered and breaks ties with Vanraj and decides to live her life on her own terms. Anupamaa's younger son, Samar also breaks all ties with Vanraj after learning the same. Rakhi informs the Shahs about the affair leaving them shattered. Soon, Anupamaa's elder son, Paritosh marries Kinjal while Samar and Nandini fall for each other after Samar learns about Nandini's infertility.

Anupamaa takes care of Vanraj's health after he meets with an accident. Vanraj develops a soft corner for Anupamaa. He tries to express his feelings to her, but Anupamaa rebukes him for it. Anupamaa decides to start afresh and tells Vanraj that she wants a divorce. Vanraj fears losing Anupamaa and his family and leaves the house. Anupamaa finds him in a wellness resort in Surat and confronts him.