With his brother, he took part in the campaign of the Byzantine catepan George Maniaches in Sicily (1038) and then in the campaign against the Greeks of Apulia with the Lombard prince Guaimar IV of Salerno. In 1042, the Normans elected William as count at Melfi and Drogo received Venosa from Guaimar in a twelve-part division of the conquered territory. In 1044–1045, Drogo fought on behalf of his brother in Apulia. He seized Bovino from the Greeks.
In 1046, when William died, Drogo and Peter of Trani were the premier candidates to succeed him. Drogo, supported by Guaimar, a good friend of William's, was duly elected as his brother's successor. The foundations of a Hauteville dynasty were set. Drogo was then approached by Ranulf Trincanocte, Count of Aversa, to reconcile him with Guaimar, which he did. In that year, he entered Apulia again and defeated the catepan Eustathios Palatinos near Taranto. His brother Humphrey, who had arrived a short while earlier, forced Bari to conclude a treaty with the Normans. In 1047, Drogo captured Benevento with the permission of the Holy Roman Emperor. It turned out to be a watershed year. First, he received a daughter of Guaimar III, named either Gaitelgrima or Altrude, as wife. Second, the Emperor Henry III confirmed him as Dux et magister Italiae comesque Normannorum totius Apuliae et Calabriae (in English, "Duke and Master of Italy and Count of the Normans of all Apulia and Calabria"), the first legitimate comital title for the Normans of Melfi. Henry also divested Guaimar of the principality of Capua and gave it to the old prince, Pandulf IV.
During Drogo's reign, his half-brother Robert Guiscard arrived in the Mezzogiorno (c.1047). Drogo remained closely allied to Guaimar and assisted him against Pandulf after the latter's reinstallation as Count of Capua. Failing to control his barons, however, Drogo was unable to end the brigandage and feudal warfare that was convulsing the Mezzogiorno. He had to send away both his own younger brother Robert and the newly-arrived Richard Drengot, who attacked him and was captured. Guaimar secured Richard's release late in 1047 or early in 1048. In the latter year, Drogo commanded an expedition into Calabria via the valley of Crati, near Cosenza. He distributed the conquered territories in Calabria and granted Robert Guiscard a castle at Scribla to guard the entrances. In 1050, he had to aid Guaimar in putting down the rebellion of one Guillaume Barbote.
In 1051, Pope Leo IX forced a promise from Drogo that he would stop the Norman pillaging, but he was assassinated later that year (probably by a Byzantine conspiracy led by Argyrus) at Montoglio and was succeeded by his younger brother Humphrey after a brief interregnum.