While employed by the Ministry of Culture in Paris, where she remained between 1981 and 1986, she produced her first novel, Le Livre des Nuits in 1985. It won six French Literary Prizes as well as the Scott Moncrieff Translations Prize in English. The reception of the book established her as a significnt new author.
From Paris she moved to Prague, Czechoslovakia, where, from 1987 to 1993, she taught philosophy at the French School, and continued to write.  In 1989, she published Jours de Colère, (Days of Anger), which won the Prix Femina.
In 1993, Sylvie Germain returned to France. She then lived between Paris and La Rochelle. But Prague continued to inspire her, a theme especially apparent in the novel Immensités, as well as the cultural life of Czech Republic more generally, as reflected in her meditation on the life and work of Bohuslav Reynek. Since 1994 she has been involved only in literary activities.
In 1999, Sylvie Germain produced a biography focusing on the life of Etty Hillesum, the young Dutch Jewish woman who died at Auschwitz in November 1943, leaving behind a journal. Germain explored her spiritual life and, a year later, she published several books in various genres: a travelogue, a spiritual text and a photo album. In 2002 she published a new novel, La Chanson des Mal-Aimants, translated in English as The Song of False Lovers.
Her 2005 novel Magnus was awarded the Prix Goncourt des Lycéens (a prize voted on by French high school students). Her most recent novel, L'inaperçu, was published by Albin Michel in August 2008.
In addition to novels, she has published essays on other artists (Vermeer: Patience et songe de lumière, 1993, for example), spiritual meditations (Les Echos du Silence) and a children's book (L'Encre du Poulpe). Most of her novels have been translated into English.