Lichtenstein then left New York to study at the Ohio State University which offered studio courses and a degree in fine arts. His studies were interrupted by a three year stint in the army during World War II and after between 1943 and 1946. Lichtenstein returned home to visit his dying father and was discharged from the army under the Servicemen's Readjustment Act (USA). Returning to studies in Ohio under the supervision of one of his teachers, Hoyt L. Sherman, who is widely regarded to have had a significant impact on his future work (Lichtenstein would later name a new studio he funded at OSU as the Hoyt L. Sherman Studio Art Center). Lichtenstein entered the graduate program at Ohio State and was hired as an art instructor, a post he held on and off for the next ten years. In 1949 Lichtenstein received a M.F.A. degree from the Ohio State University and in the same year married Isabel Wilson (divorced 1965). Wilson was previously married to Cleveland, Ohio artist Michael Sarisky. In 1951 Lichtenstein had his first one-man exhibition at Carlebach Gallery in New York. He moved to Cleveland in the same year, where he remained for six years, although frequently traveling back to New York. Undertaking jobs as varied as a draftsman to a window decorator in between periods of painting. His work at this time fluctuated between Cubism and Expressionism. In 1954 his first son, David Hoyt Lichtenstein was born. He then had his second son, Mitchell Lichtenstein in 1956. In 1957 he moved back to upstate New York and began teaching again. It was at this time that he adopted the Abstract Expressionism style, a late convert to this style of painting.
Lichtenstein began teaching in upstate New York at State University of New York at Oswego in 1958. However, the brutal upstate winters were taking a toll on him and his wife.
In 1960, he started teaching at Rutgers University where he was heavily influenced by Allan Kaprow, also a teacher at the University. This environment helped to reignite his interest in Proto-pop imagery. In 1961 Lichtenstein began his first Pop paintings using cartoon images and techniques derived from the appearance of commercial printing. This phase would continue to 1965 and included the use of advertising imagery suggesting consumerism and homemaking. His first work to feature the large-scale use of hard-edged figures and Benday Dots was Look Mickey (1961, National Gallery of Art, Washington, D.C.). This piece came from a challenge from one of his sons, who pointed to a Mickey Mouse comic book and said; "I bet you can't paint as good as that, eh, Dad?" In the same year he produced six other works with recognizable characters from gum wrappers or cartoons. In 1961 Leo Castelli started displaying Lichtenstein's work at his gallery in New York, and he had his first one man show at the gallery in 1962; the entire collection was bought by influential collectors of the time before the show even opened. Interestingly Castelli rejected the work of one of Lichtenstein's contemporaries, Andy Warhol. In September 1963 he took a leave of absence from his teaching position at Douglass College at Rutgers.
His most famous image is arguably Whaam! (1963, Tate Modern, London), one of the earliest known examples of pop art, adapted a comic-book panel from a 1962 issue of DC Comics' All-American Men of War. The painting depicts a fighter aircraft firing a rocket into an enemy plane, with a red-and-yellow explosion. The cartoon style is heightened by the use of the onomatopoeic lettering "Whaam!" and the boxed caption "I pressed the fire control... and ahead of me rockets blazed through the sky..." This diptych is large in scale, measuring 1.7 x 4.0 m (5 ft 7 in x 13 ft 4 in).
Most of his best-known artworks are relatively close, but not exact, copies of comic-book panels, a subject he largely abandoned in 1965. (He would occasionally incorporate comics into his work in different ways in later decades.) These panels were originally drawn by such comics artists as Jack Kirby and DC Comics artists Russ Heath, Tony Abruzzo, Irv Novick, and Jerry Grandenetti, who rarely received any credit. Jack Cowart, executive director of the Lichtenstein Foundation contests the notion that Lichtenstein was a copyist, saying: "Roy's work was a wonderment of the graphic formulae and the codification of sentiment that had been worked out by others. The panels were changed in scale, color, treatment, and in their implications. There is no exact copy."
In 1967 his first museum retrospective exhibition was held at the Pasadena Art Museum in California. Also in this year his first solo exhibition in Europe was held at museums in Amsterdam, London, Bern and Hannover. He married his second wife, Dorothy Herzka in 1968.
In the 1970s and 1980s, his work began to loosen and expand on what he had done before. He produced a series of "Artists Studios" which incorporated elements of his previous work. A notable example being Artist's Studio, Look Mickey (1973, Walker Art Center, Minneapolis) which incorporates five other previous works, fitted into the scene.
In addition to paintings, he also made sculptures in metal and plastic including some notable public sculptures such as Lamp in St. Mary’s, Georgia in 1978, and over 300 prints, mostly in screenprinting.
His painting Torpedo...Los! sold at Christie's for $5.5 million in 1989, a record sum at the time, making him one of only three living artists to have attracted such huge sums.
In 1996 the National Gallery of Art in Washington DC became the largest single repository of the artist's work when he donated 154 prints and 2 books. In total there are some 4,500 works thought to be in circulation.
He died of pneumonia in 1997 at New York University Medical Center.
Among many other works of art destroyed in the World Trade Center attacks on September 11, 2001, a painting from Roy Lichtenstein’s The Entablature Series was destroyed in the fire.