Piso was the son of Lucius Calpurnius Piso, who had been forced to change his praenomen from Gnaeus to Lucius due to his father's involvement in a conspiracy against Tiberius. The life of the younger Piso is not well known prior to his accession to consul in 57 as the colleague of Emperor Nero. Tacitus records an incident in the previous year where a conflict arose between the praetor Vibullius and Antistius Sosianus, the plebeian tribune, over whether to keep imprisoned some disorderly audience members; the Senate ruled against Antistius, and Piso went further and proposed that tribunes would no longer be permitted to try cases in their own houses.
While governing Roman Africa, the civil war known as the Year of Four Emperors erupted. Both the province and Piso supported Vitellius, who had been proconsul there not long before. The commander of the legion stationed in North Africa, Gaius Calpetanus Rantius Quirinalis Valerius Festus, however, was in secret communication with Vespasian. Following the death of Vitellius, Claudius Sagitta, a prefect of horse, reached Africa. Sagitta told Piso that an order had been issued to put the proconsul to death, that his son-in-law had been executed, and Piso's only hope of safety was to either flee to those supporters of Vitellius who remained in Gaul and Spain, or to defend himself in Carthage; Piso was not moved by this news. Shortly afterwards a messenger, Gaius Licinius Mucianus, arrived as an envoy from Mucianus, a partisan of Vespasian based in Rome, to parlay with Piso. Piso refused to leave his palace, which incensed the local population, who began to riot in the marketplace, demanding that Piso present himself. Piso avoided showing himself to the crowd, but managed to have the messenger brought to him, and on questioning him found that Mucianus had dispatched him to kill him. The proconsul ordered the messenger executed and refused to discharge any duties outside the palace, as an attempt to guard against a repeat of the riot. When Festus learned of the events in Carthage, he sent a troop of cavalry to murder Piso. Although none of the men knew Piso, he was identified for them by Baebius Massa, whom Tacitus described as "a man even then fatal to the good, and destined often to reappear among the course of the sufferings which he had ere long to endure." With Piso dead Festus was able to take control of the province and openly declared for Vespasian.
