Aspasia was legally forbidden to marry an Athenian citizen on two counts: as a hetaera, and as a foreigner. She became the mistress of the statesman Pericles, however, and when he divorced his first wife (c. 445 BCE), Aspasia began to live with him as if they were married. After Pericles' two sons from his first marriage died of the plague in 429, the son he had with Aspasia, Pericles the younger, obtained Athenian citizenship. (This son was later elected general, and was one of the generals executed after the botched Battle of Arginusae.)

Their house became an intellectual centre in Athens, attracting the most prominent writers and thinkers, including the philosopher Socrates. The attraction wasn't merely the powerful and brilliant Pericles, for Aspasia was not only beautiful, but intelligent and skilled in writing and speech; moreover, she was believed to have great political influence. Although none of her writing survives, she was openly credited by writers such as Plato and Aeschines Socraticus with making a significant contribution to Pericles' skill in oratory and politics; there was even gossip to the effect that she helped pen Pericles' famous Funeral Speech, transmitted to us by Thucydides. On the basis that she might have been a teacher of the art of rhetoric and politics to many students, including Socrates (according to Plato's dialogue the Menexenus), some scholars believe that Aspasia even invented the Socratic method.

Her political influence also brought her unpopularity; she was said (mainly by comic playwrights of the time), for example, to be responsible for the Samian revolt of 440 BCE, and for the Peloponnesian War with Sparta (431–404 BCE). She was not only attacked by the comic playwrights, but was accused of impiety by Hermippus, a comic poet. (We do not know the nature of this attack, whether it appeared in a play or in an actual lawsuit.)

Plato was so impressed by her intelligence and wit that he is thought to have based his character Diotima on her (see his Symposium). Aeschines Socraticus and Antisthenes each named a Socratic dialogue after Aspasia (though neither survives except in fragments).

After Pericles' death in 429 BCE, Aspasia married the democrat Lysicles, with whom she had another son. Aeschines Socraticus is said to have credited Aspasia with Lysicles' political success.