On his return to Rome two years later, the outbreak of the civil war between Caesar and Gnaeus Pompeius Magnus saved Cassius from being brought to trial by his enemies for extortion in Syria. Cassius was elected tribune of the Plebs in 49 BC, and threw in his lot with the Optimates, fleeing Italy as Caesar crossed the Rubicon. He met Pompey in Greece, and was made commander of his fleet. In 48 BC, Cassius sailed his ships to Sicilia where he attacked and burned a large part of Caesar's navy. He then proceeded to harass ships off the Italian coast. News of Pompey's defeat at the Battle of Pharsalus caused Cassius to head for Hellespont, with hopes of allying with its king, Pharnaces II. Cassius was overtaken by Caesar en route, and was forced to surrender unconditionally.
Caesar made Cassius a legate, employing him in the Alexandrian War against the very same Pharnaces Cassius had hoped to join. However, Cassius refused to join in the fight against Cato and Scipio in Africa, choosing instead to retire to Rome. He spent the next two years without office, and apparently tightened his friendship with Cicero. In 44 BC he became Praetor Peregrinus with the promise of the Syrian province for the ensuing year. The appointment of his junior, Marcus Junius Brutus, as praetor urbanus deeply offended him, and only deepened the hatred and resentment Cassius felt for the dictator. Caesar, though still officially forgiving of Cassius, seems to have mistrusted him. He was one of the busiest conspirators against Caesar, winning over the chief assassins to the cause of tyrannicide. On the Ides of March, 44 BC, Cassius urged on his fellow assassins, and struck Caesar in the face. He and his fellow conspirators referred to themselves as the "Liberators" (Liberatores). The celebration was short-lived, as Antony seized power and turned the public against them.
In April, Cassius fled Rome for the countryside, hoping that Antonius would be overthrown. In June, the Senate assigned Cassius the province of Cyrene in order to give him clearance to leave Italy while retaining his office as praetor. Cassius balked at being given such a small province and resigned his office, stating that he would rather live in exile than under Antonius. He left for his previously assigned province of Syria, which had been reassigned to Publius Cornelius Dolabella at Antony's behest, hoping to take control of it before Dolabella arrived. His reputation in the East made it easy to amass an army from other governors in the area, and by 43 BC he was ready to take on Dolabella with 12 legions. By this point the Senate had split with Antony and cast its lot with Cassius, confirming him as governor of the province. Dolabella attacked but was betrayed by his allies, leading him to commit suicide. Cassius was now secure enough to march on Egypt, but on the formation of the triumvirate, Brutus requested his assistance. Cassius quickly joined Brutus in Smyrna with most of his army, leaving his nephew behind to govern Syria. The conspirators decided to attack the triumviri’s allies in Asia. Cassius set upon and sacked Rhodes, while Brutus did the same to Lycia. They regrouped the following year in Sardis, where their armies proclaimed them imperators. They crossed the Hellespont, marched through Thrace, and encamped near Philippi in Macedon. Gaius Julius Caesar Octavian (later known as Augustus) and Marcus Antonius soon arrived, and Cassius planned to starve them out through the use of their superior position in the country. However, they were forced into a pair of battles by Antony, collectively know as the Battle of Philippi. Brutus was successful against Octavian, and took his camp. Cassius, however, was defeated and overrun by Marcus Antonius. Cassius, unaware of Brutus' victory, gave up all for lost, and ordered his freedman Pindarus to slay him. He was mourned by Brutus as "the Last of the Romans" and buried in Thasos.