Manfred was born in Venosa. Frederick II appears to have regarded him as legitimate, and by his will named him as Prince of Taranto. Frederick named Manfred's half-brother Conrad IV king of Germany, Italy and Sicily, but Manfred was regent of Sicily while Conrad was in Germany. Manfred, who initially bore his mother's surname, studied in Paris and Bologna and shared with his father a love of poetry and science.
At Frederick's death in 1250, Manfred, although only about 18 years old, acted loyally and with vigour in the execution of his trust. The Kingdom was in turmoil, mainly due to rebellions spurred by Pope Innocent IV. Manfred was able to subdue numerous rebel cities, with the exception of Naples. Manfred attempted in 1251 to make concessions to Innocent IV to stave off the prospect of war, but the attempt failed. When Conrad IV, Manfred's legitimate brother, appeared in southern Italy in 1252, his authority was quickly and generally acknowledged. Conrad quickly stripped Manfred of all his fiefs by limiting his authority solely to the principality of Taranto. Naples fell in October 1253 into the hands of Conrad. Conrad made the pope Conradin's guardian, and named the Margrave
Berthold of Hohenberg, a powerful German baron, as regent of Conradin, his infant son.[A]
In May 1254 Conrad died of malaria at the age of twenty-six. Manfred, after refusing to surrender Sicily to Innocent IV, accepted the regency on behalf of Conradin. The pope however, having been named guardian of Conradin, excommunicated Manfred in July 1254. The regent decided to open negotiations with Innocent. As part of a treaty made in September 1254, Manfred submitted, and accepted the title of Papal vicar for southern Italy But Manfred’s suspicions being aroused by the demeanour of the papal retinue, and also annoyed by the occupation of Campania by papal troops, he fled to the Saracens at Lucera. Aided by Saracen allies, he defeated the papal army at Foggia on 2 December 1254, and soon established his authority over Sicily and the Sicilian possessions on the mainland. In that year Manfred supported the Ghibelline communes in Tuscany, in particular Siena, to which he provided a corps of German knights that was later instrumental in the defeat of Florence at the Battle of Montaperti. He thus reached the status of patron of the Ghibelline League. Also in that year Innocent died, succeeded by Alexander IV, who immediately excommunicated Manfred. In 1257, however, Manfred crushed the papal army and settled all the rebellions, imposing his firm rule of southern Italy and receiving the title of vicar from Conradin.