The novel deals with themes of betrayal, faith, family, marriage, Imperial Russian society, desire, and rural vs. urban life. The story centers on an extramarital affair between Anna and dashing cavalry officer Count Alexei Kirillovich Vronsky that scandalizes the social circles of Saint Petersburg and forces the young lovers to flee to Italy in a search for happiness, but after they return to Russia, their lives further unravel.

Trains are a motif throughout the novel, with several major plot points taking place either on passenger trains or at stations in Saint Petersburg or elsewhere in Russia. The story takes place against the backdrop of the liberal reforms initiated by Emperor Alexander II of Russia and the rapid societal transformations that followed. The novel has been adapted into various media including theater, opera, film, television, ballet, figure skating, and radio drama.

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