Tri sestre se ubadajo z ljubeznijo in družinskimi vezmi. Mia Farrow in Michael Caine sta zakonca, Barbara Hershey je njena sestra, ki se zaplete s svakom, tretja sestra Dianne Wiest pa z njenim nekdanjim možem Woodyjem Allenom.Manhattanski mozaik osebnih odnosov "Hannah in njeni sestri" spremlja življenje, ljubezni in nezvestobo znotraj povezanega umetniškega družinskega klana. Hannah (Mia Farrow) se redno sestaja s svojima sestrama Holly (Dianne Wiest) in Lee (Barbara Hershey), ko razpravljajo o dogodkih minulega tedna. Tisto, česar si ne zaupajo, sestavlja mnoge pripovedne niti filma. Hannah je poročena z računovodjo in finančnim svetovalcem Elliotom (Michael Caine), ki se ogreje za njeno sestro Lee, ta pa živi s starejšim, ekscentričnim umetnikom iz Soha Frederickom (Max Von Sydow). Medtem se Holly, nevrotična igralka in večna zguba v ljubezni, videva s televizijskim producentom Mickeyjem (Woody Allen), nekdanjim soprogom Hannah, ki večino časa vsakomur razlaga, kako bo vsak čas umrl. Zgodba se začne in konča med tradicionalno družinsko večerjo na zahvalni dan. Legendarni film Woodyja Allena je bil posnet v resničnem stanovanju Mie Farrow v New Yorku.
Hannah, Holly and Lee are adult sisters from a show business family, their boozy actress mother who still believes she's an ingénue that can attract any man she wants, despite still being married to the girls' father, Evan. Hannah, on her second marriage to a man named Elliot, a financial advisor, is the success of the family, taking a break from her acting career to raise her children. Everyone turns to her for advice, while she never talks to others about what she needs or feels. Her first husband, Mickey, is a comedy show writer and hypochondriac, who is going through a crisis as he mistakenly believes he will die soon without a clear belief, as a non-practicing Jew, of what will happen to him in the afterlife. Single Holly is the insecure flaky sister, a struggling and thus continually unemployed actress, who has just started a catering business with her actress friend April, in order to do something constructive with her life. In her own security, Hannah even set up Holly and Mickey together following her own break-up with Mickey, Holly and Mickey's sole date which arguably was the worst night in both their lives. Holly turns to Hannah for everything in her life, including money, despite feeling Hannah overly judgmental about her failures. It's during a catering job that Holly and April meet David, an architect, who seems interested in both of them. Holly's insecurities may threaten her potential relationship with David and friendship with April. Lee, who collects unemployment, is metaphorically the family's piece of clay waiting for the right artist to mold her. She has long lived with artist Frederick, who has contempt for everyone except her, and as such relies on her for whatever his connection to the outside world. This already complex collective becomes even more complex when Elliot contemplates telling Lee that he has fallen in love with her. His attraction to her is as much feeling unneeded by Hannah, who he does not want to hurt regardless of what he d