Waller was educated at Eton College and the University of Cambridge and entered Parliament while still a young man. In 1631 he married the heiress of a wealthy London merchant, but she died three years later. He then paid unsuccessful court to Lady Dorothy Sidney (whom he addressed in poetry as Sacharissa) and in 1644 married Mary Bracey.

During the political turmoil of the 1640s, with Parliament arrayed against the King, Waller was at first a champion of religious toleration and an opponent of the bishops. He then drifted to the King's cause, and in 1643 he was deeply involved in a conspiracy (sometimes known as Waller's plot) to establish London as a stronghold of the King, leading to the poet's arrest in May. By wholesale betrayal of his colleagues, and by lavish bribes, he managed to avoid the death sentence, but he was banished and heavily fined. He then lived abroad until 1651, when he made his peace with his distant cousin Oliver Cromwell, later lord protector of the Commonwealth.

Several of Waller's poems, including “Go, lovely Rose!”—one of the most famous lyric poems in English literature—had circulated for some 20 years before the appearance of his Poems in 1645. The first edition claiming full authorization, however, was that of 1664. In 1655 appeared his “Panegyrick to my Lord Protector” (i.e., Cromwell), but in 1660 he also celebrated “To the King, upon his Majesties happy return.” He became a member of the Royal Society and was returned to Parliament in 1661, where he held moderate opinions and advocated religious toleration. His later works include Divine Poems (1685). The Second Part of Mr. Waller's Poems was published in 1690.

Waller's poetry was held in high esteem throughout the 18th century, but his reputation waned in the 19th century along with that of Augustan poetry in general. His technical achievement in leading away from the dense verse of the Metaphysical poets (Metaphysical poet) lies in his incorporation of wit more related to rational judgment and in his replacement of Metaphysical poetry's dramatic immediacy, argumentative structure, and ethical seriousness with generalizing statement, easy associative development, and urbane social comment. His pursuit of definitive phrasing through inversion and balance led to the tight, symmetrical patterning of the Augustan heroic couplet. Waller helped to transmit to the Augustans a synthesis of the regular iambic norm with native English four-stress alliterative metre and showed its use for expressive emphasis, as in the line “Invíte affećtion, and restráin our ráge.” Waller is also remembered for the distinction of his poems on public themes and for his elegance, lyrical grace, and formal polish.