His first fully achieved paintings were based on imagery from comic strips and advertisements and rendered in a style mimicking the crude printing processes of newspaper reproduction.

These paintings reinvigorated the American art scene and altered the history of modern art. Lichtenstein’s success was matched by his focus and energy, and after his initial triumph in the early 1960s, he went on to create an oeuvre of more than 5,000 paintings, prints, drawings, sculptures, murals and other objects celebrated for their wit and invention.

During the 1960s, along with Andy Warhol, Jasper Johns, and James Rosenquist among others, he became a leading figure in the new art movement.

His work defined the premise of pop art through parody. Inspired by the comic strip, Lichtenstein produced precise compositions that documented while they parodied, often in a tongue-in-cheek manner.

His work was influenced by popular advertising and the comic book style. He described pop art as "not 'American' painting but actually industrial painting". His paintings were exhibited at the Leo Castelli Gallery in New York City.

Whaam! and Drowning Girl are generally regarded as Lichtenstein's most famous works, with Oh, Jeff...I Love You, Too...But... arguably third.

Drowning Girl, Whaam! and Look Mickey are regarded as his most influential works. His most expensive piece is Masterpiece, which was sold for $165 million in January 2017.