Born in 1868 in Nancy, to a Jewish family of the middle bourgeoisie, long established in Lorraine, Spire studied literature, then law.
A few months later, the Dreyfus Affair broke when a Jewish military officer was wrongly accused of treason, revealing how widespread antisemitism was at the time in France.
Spire provoked a duel with a columnist from the Libre Parole (a nationalist and antisemitic newspaper run by Edouard Drumont) for alleging that the Jews appointed to the Conseil d'État won their positions not on merit but through illicit influence.
Spire left the Conseil d'Etat for the ministry of Labour, then joined the staff of Jean Dupuy, Minister of Agriculture in the government of Waldeck-Rousseau.
Following the defeat of France in 1940, Spire was forced into exile in the United States of America where he was invited to teach French Literature at the New School for Social Research and the École libre des Hautes études in New York.