She was born in Nancy, the daughter of Henry II, Duke of Lorraine and Bar, and Margherita Gonzaga.

In the absence of a son, Margherita and Henry attempted to secure the inheritance of Lorraine and Bar for their eldest daughter Nicole.

However, Francis, Count of Vaudémont (Henry II's younger brother) refused Nicole's right by claiming that the Salic law applied in Lorraine.

When Louis XIII sent an army under Louis de Marillac to the Duchy, however, Francis managed to win over the support of the States-General of Lorraine, who were afraid of France, and they declared him duke on 21 November 1625, deposing Nicole; five days later he abdicated in favor of his son, who became Charles IV of Lorraine.

[4] In December 1627, Nicole's maternal uncle Vincenzo II Gonzaga died, after which the War of the Mantuan Succession began.

Nicole separated from her husband and settled in Paris, where she enjoyed the support of the French royal court.