After the triumphal Macedonian victory at the Battle of Chaeronea in 338 BC, Antipater was sent as ambassador to Athens (337–336 BC) to negotiate a peace treaty and return the bones of the Athenians who had fallen in the battle.
He started as a great friend to both the young Alexander and the boy's mother, Olympias; there were even rumours that he was Alexander's father. He aided Alexander in the struggle to secure his succession after Philip's death, in 336 BC.
He joined Parmenion in advising Alexander the Great not to set out on his Asiatic expedition until he had provided by marriage for the succession to the throne. On the king's departure in 334 BC, he was left regent in Macedonia and made "general (strategos) of Europe", positions he held until 323 BC. The European front was to prove initially quite agitated, and Antipater also had to send reinforcements to the king, as he did while the king was at Gordium in the winter of 334–333 BC.
The Persian fleet under Memnon of Rhodes and Pharnabazus was apparently a considerable danger for Antipater, bringing war in the Aegean sea and threatening war in Europe. Luckily for the regent, Memnon died during the siege of Mytilene on the isle of Lesbos and the remaining fleet dispersed in 333 BC, after Alexander's victory at the Battle of Issus.
More dangerous enemies were nearer home; tribes in Thrace rebelled in 332 BC, lead by Memnon of Thrace, the Macedonian governor of the region, followed shortly by the revolt of Agis III, king of Sparta.
The Spartans, who were not members of the League of Corinth and had not participated in Alexander's expedition, saw in the Asian campaign the long awaited chance to take back control over the Peloponnese after the disastrous defeats at the Battle of Leuctra and Battle of Mantinea. The Persians generously funded Sparta's ambitions, making possible the formation of an army 20.000 strong. After assuming virtual control of Crete, Agis tried to build an anti-Macedonian front. While Athens remained neutral, the Achaeans, Arcadians and Elis became his allies, with the important exception of Megalopolis, the staunchly anti-Spartan capital of Arcadia. Agis started in 331 BC to besiege the city with his entire army, generating great alarm in Macedon.
So to not have two enemies simultaneously, Antipater pardoned Memnon and even let him keep his office in Thrace, while great sums of money were sent him by Alexander. This helped to create, with Thessalian help and many mercenaries, a force double that of Agis, which Antipater in person led south in 330 BC to confront the Spartans. In the spring of that year, the two armies clashed near Megalopolis. Agis fell with many of his best soldiers, but not without inflicting heavy losses on the Macedonians.
Utterly defeated, the Spartans sued for peace; the latter's answer was to negotiate directly with the League of Corinth, but the Spartan emissaries preferred to treat directly with Alexander, who imposed on Sparta's allies a penalty of 120 talents and the entrance of Sparta in the league.
Alexander appears to have been quite jealous of Antipater's victory; according to Plutarch, the king wrote in a letter to his viceroy: "It seems, my friends that while we have been conquering Darius here, there has been a battle of mice in Arcadia".
Antipater was disliked for supporting oligarchs and tyrants in Greece, but he also worked with the League of Corinth, built by Philip. In addition, his previously close relationship with the ambitious Olympias greatly deteriorated. Whether from jealousy or from the necessity of guarding against the evil consequences of the dissension between Olympias and Antipater, in 324 BC, Alexander ordered the latter to lead fresh troops into Asia, while Craterus, in charge of discharged veterans returning home, was appointed to take over the regency in Macedon. When Alexander suddenly died in Babylon in 323 BC however, Antipater was able to forestall the transfer of power.