Seleucus was the son of Antiochus, a general of Philip II of Macedonia, the father of Alexander the Great. Seleucus participated in the conquest of the Persian empire as one of Alexander's officers, and in 326 he commanded the Macedonian infantry against King Porus of India in battle on the Hydaspes River. In 324 Alexander ordered a mass wedding ceremony at Susa (in Persia) to put into practice his ideal of uniting the peoples of Macedonia and Persia. On this occasion Seleucus married Apama, the daughter of Spitamenes, the ruler of Bactria. Of all the Macedonian nobles, he was the only one who did not repudiate his wife after Alexander's death.

After Alexander died (323), Seleucus was given the command of the hetairoi (companions) cavalry and took part in the regent Perdiccas' (Perdiccas) campaign to oust Ptolemy (Ptolemy I Soter), the governor (satrap) of Egypt. In Egypt, however, he joined with others in the assassination of Perdiccas. When the empire was divided in 321, he was given the governorship (satrapy) of Babylon. At the same time Antigonus Monophthalmus (Antigonus I Monophthalmus) (the One-Eyed) had been placed in command of a campaign against Eumenes of Cardia, a supporter of Perdiccas. In 317 Seleucus aided Antigonus but, after Eumenes' execution in 316, Antigonus demanded that Seleucus give an accounting of the income from his satrapy. Seleucus refused to give the accounting and escaped capture by fleeing to Ptolemy in Egypt.

From 316 to 312 Seleucus remained in Ptolemy's service. He took the initiative in forging a coalition among Ptolemy, Lysimachus (the ruler of Thrace), and Cassander (who laid claim to Macedonia) against Antigonus, whose desire to become the ruler of the whole of Alexander's empire was a threat to them all. In the resulting coalition war (315–311), Seleucus was made one of Ptolemy's generals and jointly with him commanded the Ptolemaic troops that defeated the force of Demetrius, the son of Antigonus, at the Battle of Gaza in southern Syria (312).

Seleucus once again turned his attention to returning to Babylonia, and in August 312 he was able to reconquer Babylon with only a small army. This conquest marked the beginning of the Seleucid era, which is dated Dios 1 (Oct. 7), 312, in the Macedonian calendar and Nisan 1 (April 3), 311, in the Babylonian calendar. Antigonus ordered Nicanor, one of his generals, to invade Babylonia from the east and his son Demetrius to attack it from the west, but they failed to oust Seleucus. When Antigonus made peace with his enemies in 311, Seleucus was not included.

Little is known about the next few years of Seleucus' reign; he presumably used them to consolidate his gains. In the year 305 he followed the example of the other successors and assumed the title of king (basileus). He embarked on an expansion of his kingdom throughout the Iranian east (the upper satrapies) as far as India, but his advance was eventually halted by Candragupta (Chandra Gupta), the founder of the Maurya dynasty of India. In a pact concluded by the two potentates, Seleucus agreed to territorial concessions in exchange for 500 elephants.

Developments in the west also caused Seleucus to end his campaign in India (303). He had joined a coalition that Ptolemy, Cassander, and Lysimachus had once again formed against Antigonus and Demetrius. In the winter of 302 Seleucus was back in Asia Minor and, together with Cassander and Lysimachus, defeated Antigonus in the Battle of Ipsus (Ipsus, Battle of) (301). The victors divided the lands of their enemy among them, with Seleucus being given Syria. The southern part of Syria, Coele Syria, had in the meantime been occupied by Ptolemy, who had not taken part in the war. This gave rise to the long series of Syrian Wars between the Seleucids and Ptolemies. For the time being, however, Seleucus declined to enforce his claim; he merely transferred his capital from Seleucia on the Tigris to the newly founded city of Antioch on the Orontes (301–300).

Ptolemy, anxious to improve relations with Lysimachus, had given him his daughter Arsinoe in marriage. To provide a counterbalance, Seleucus asked for the hand of Stratonice, the daughter of Demetrius, and in 298 the wedding was held with much pomp at Rhosus in Syria. Soon, however, Seleucus' territorial demands (e.g., the surrender of Cilicia and the cities of Tyre and Sidon) ruptured the previously harmonious relationship with Demetrius.

In 294 a sensational scandal occurred at the court of Seleucus. Antiochus (Antiochus I Soter), his son by Apama, fell in love with his beautiful stepmother, Stratonice, and his unrequited passion affected his health. Seleucus gave him Stratonice, assigned him as commander in chief to the upper satrapies, and appointed him co-regent.

In 285 Seleucus took Demetrius prisoner, thus foiling his attempt to conquer Asia, and interned him in Apamea, where he died in 283. Subsequently, Seleucus intervened in dissensions in the house of Lysimachus, who had had his son Agathocles assassinated. In February 281 Lysimachus fell in a battle against Seleucus at Corupedium, and Seleucus gained control of Lysimachus' kingdom. He was now near his goal of reestablishing Alexander's empire. He crossed over to Europe to enter Macedonia, but at the end of August or beginning of September 281, he was murdered by Ptolemy Ceraunus, who had been passed over by his father, Ptolemy, as successor to the Egyptian throne. Seleucus' son and successor, Antiochus I, entombed his father's ashes in Seleucia, initiated (probably) the posthumous cult of his father, and ordered his veneration as Zeus Nicator.

Seleucus was an energetic ruler, creating the Seleucid Empire, which gained its greatest expansion under his rule. He took great interest in the administration of his territories and founded many new cities. He also encouraged scientific research: Patrocles explored the Caspian Sea and Megasthenes the Ganges River. A bronze bust—a very impressive likeness of him, conveying his imposing personality—was found in Herculaneum (in Italy) and is now in Naples.