The reign of Cleopatra VII of the Ptolemaic Kingdom of Egypt began with the death of her father, Ptolemy XII Auletes, by March 51 BC. It ended with her suicide in August 30 BC, which also marked the conclusion of the Hellenistic period and the annexation of Egypt into a Roman province. In the style of her Greek predecessors, Cleopatra reigned over Egypt and other territories as an absolute monarch, although the Roman Republic frequently interfered in its internal affairs. Her personal rule of Egypt was characterized by a continued reliance on agriculture, extensive trade and conflict with other states, the tackling of corruption, strategic management of the bureaucracy, and ambitious building projects.

Cleopatra initially acceded to the throne alongside her younger brother Ptolemy XIII, but a fallout between them led to open civil war. Further chaos ensued when the Roman consul Julius Caesar pursued his rival Pompey into Ptolemaic Egypt, a Roman client state. Upon arrival, Caesar discovered that Pompey had been assassinated on the orders of Ptolemy XIII. Caesar attempted to reconcile the siblings, but a discontent Ptolemy XIII and his adviser Potheinos raised forces against Caesar and Cleopatra. Reinforcements lifted the siege in early 47 BC, and Ptolemy XIII died shortly afterwards in the Battle of the Nile. Arsinoe IV (Cleopatra's younger sister and a rival claimant to the throne) was exiled, and Caesar, now dictator, declared Cleopatra and her younger brother Ptolemy XIV co-rulers of Egypt. However, Caesar maintained a private affair with Cleopatra that produced a son, Caesarion, before he departed Alexandria for Rome.

Cleopatra visited Rome as a client queen in 46 and 44 BC; following Caesar's assassination in 44 BC, Cleopatra attempted to have Caesarion named as his heir, which was thwarted by Caesar's grandnephew Octavian. Cleopatra then had Ptolemy XIV killed and elevated Caesarion as her co-monarch. In the Liberators' civil war of 43–42 BC, Cleopatra sided with the Second Triumvirate and developed a personal relationship with Mark Antony, one of its members, that would produce three children. Antony continually used his triumviral authority to the benefit of Cleopatra and became increasingly reliant on her for funding and military aid during his invasions of various eastern domains. The 34 BC Donations of Alexandria, in which Cleopatra and her children received various titles and territories under Antony's triumviral authority, along with Antony's divorce of Octavian's sister Octavia, marked a turning point that led to Octavian declaring war on Cleopatra. In 31 BC, Antony and Cleopatra led a joint naval force at Actium against Octavian's general Agrippa, who won after they fled the battle. Octavian's forces invaded Egypt the following year. Although the couple offered military resistance, Octavian defeated their forces, driving Antony to suicide. When Cleopatra learned that Octavian intended to transport her to Rome as a prisoner in his triumphal procession, she likewise committed suicide, reportedly through poisoning.

Ptolemy XII Auletes, ruling pharaoh of the Ptolemaic Kingdom of Egypt, designated in his will that his daughter Cleopatra VII should reign alongside her brother Ptolemy XIII as co-rulers in the event of his death. On 31 May 52 BC, Cleopatra was made a regent of Ptolemy XII as indicated by an inscription in the Temple of Hathor at Dendera. Duane W. Roller asserts that Ptolemy XII perhaps died sometime before 22 March 51 BC, while Joann Fletcher offers the date 7 March 51 BC. Michael Grant states it could have occurred as late as May of that year. Cleopatra's first known act as queen occurred on 22 March 51 BC. She traveled to Hermonthis, near Thebes, to install a new sacred Buchis bull, worshiped as an intermediary for the god Montu in the Ancient Egyptian religion. The Roman Senate, which viewed Ptolemaic Egypt as a client state, was not informed of the death of Ptolemy XII until 30 June or 1 August 51 BC. This was most likely an attempt by Cleopatra to suppress this information and consolidate power.

Cleopatra perhaps wedded her brother Ptolemy XIII, but it is unknown if their marriage ever took place. By 29 August 51 BC, official documents began listing Cleopatra as the sole ruler, evidence that she had rejected her brother as a co-ruler by this point. Cleopatra faced several pressing issues and emergencies shortly after taking the throne. These included food shortages and famine caused by drought and low-level flooding of the Nile and assaults by gangs of armed brigands. Another problem was the lawless behavior instigated by the Gabiniani, the now unemployed, assimilated, and largely Germanic and Gallic Roman soldiers left by Aulus Gabinius to garrison Egypt after restoring Ptolemy XII and removing his daughter Berenice IV from power. As an astute financial administrator of her kingdom, Cleopatra eventually brought the combined wealth of tax revenues and foreign trade up to 12,000 talents a year, surpassing the wealth creation of some of her Ptolemaic predecessors. In the meantime, however, she inherited her father's debts and owed the Roman Republic 17.5 million drachmas by the time Julius Caesar arrived at Alexandria in 48 BC.

In 50 BC, Marcus Calpurnius Bibulus, proconsul of Syria, sent his two eldest sons to Egypt, most likely to negotiate with the Gabiniani and recruit them as soldiers in the desperate defense of Syria against the Parthians. However, the Gabiniani tortured and murdered them, perhaps with secret encouragement by rogue senior administrators in Cleopatra's court such as the eunuch-regent Potheinos. This led her to send the Gabiniani culprits to Bibulus as prisoners awaiting his judgment. Although a seemingly shrewd act by the young queen, Bibulus sent the prisoners back to her and chastised her for interfering in Roman affairs that should have been handled directly by the Roman Senate. Bibulus, siding with Pompey the Great in Caesar's Civil War, was then charged with preventing Caesar from landing a naval fleet in Greece. He failed at the task, which ultimately allowed Julius Caesar to reach Egypt in pursuit of Pompey.

Although Cleopatra had rejected her 11-year-old brother as a joint ruler in 51 BC, Ptolemy XIII still retained strong allies, including Potheinos, his tutor and administrator of his properties. The Romans, including Caesar, initially viewed him as the power behind the throne. Others involved in the cabal against Cleopatra included Achillas, a prominent military commander, and Theodotus of Chios, another tutor of Ptolemy XIII. Cleopatra seems to have attempted a short-lived alliance with her brother Ptolemy XIV, but by October of 50 BC, Ptolemy XIII had the upper hand in their conflict and began signing documents with his name before that of his sister, followed by the establishment of his first regnal date in 49 BC.

Cleopatra and her forces were still holding their ground against Ptolemy XIII within Alexandria when Gnaeus Pompeius, son of Pompey, arrived at Alexandria in the summer of 49 BC seeking military aid on behalf of his father. After returning to Italy from the wars in Gaul and crossing the Rubicon in January of 49 BC, Caesar forced Pompey and his supporters to flee to Greece in a Roman civil war. In perhaps their last joint decree, both Cleopatra and Ptolemy XIII agreed to Gnaeus Pompeius' request. They sent his father 60 ships and 500 troops, including the Gabiniani, a move that helped erase some of the debt owed to Rome by the Ptolemies. The Roman writer Lucan claimed that by early 48 BC, Pompey named Ptolemy XIII as the legitimate sole ruler of Egypt; whether true or not, Cleopatra was forced to flee Alexandria and withdraw to the region of Thebes. However, by the spring of 48 BC, Cleopatra traveled to Syria with her younger sister Arsinoe IV to gather an invasion force that would head to Egypt. She returned with an army, perhaps right around the time of Caesar's arrival, but her brother's forces, including some Gabiniani, mobilized to fight against her. They blocked her advance to Alexandria, and she had to make camp outside Pelousion in the eastern Nile Delta.