The son of an Indiana governor, Wallace left school at 16 and became a copyist in the county clerk's office, reading in his leisure time. He began his study of law in his father's office but left to recruit volunteers for the Mexican War, in which he served from 1846 to 1847. In 1849, already a practicing attorney in Indianapolis, he was admitted to the bar. In the American Civil War he served with the Union forces and attained the rank of major general of volunteers. At the Battle of Monocacy (Monocacy, Battle of) (July 9, 1864), he was defeated by the Confederate general Jubal A. Early but nevertheless prevented the latter from capturing the Federal capital, Washington, D.C. He served as president of the courts of inquiry that investigated the conduct of the Union general D.C. Buell and condemned the Confederate captain Henry Wirz, commander of the notorious Confederate prisoner-of-war camp at Andersonville, Ga. He was a member of the court that tried the persons charged with assassinating President Abraham Lincoln. In 1865 Wallace resigned from the army and returned to law practice. He held two diplomatic positions by presidential appointment. He was governor of New Mexico (1878–81), and then minister to Turkey (1881–85).

Though Wallace also wrote poetry and a play, his literary reputation rests upon three historical novels: The Fair God (1873), a story of the Spanish conquest of Mexico; The Prince of India (1893), dealing with the Wandering Jew and the Byzantine Empire; and above all Ben-Hur (1880), a romantic tale set in the Roman Empire during the coming of Christ. Its main character, a young Jewish patrician named Judah Ben Hur, loses his family and freedom because of the injustice of a Roman officer but eventually triumphs through his own abilities and the intervention of Jesus. Ben-Hur was an enormous popular success and was made into a play and a motion picture (1925) and then remade on a spectacular scale in another motion-picture version (1959). Lew Wallace: An Autobiography was published in 1906.