Some common subjects of Margaret Keane's work include women, children and animals, all of which are painted with oversized, emotive eyes. The paintings are usually done in oil or mixed media.
Though Keane's paintings tend to be cute and innocent, they also have an undercurrent of melancholy due to the subjects' soulful eyes and expressions. A typical composition of one of Keane's paintings features a large figure in the foreground that dominates most of the painting. The background may feature flowers or a peaceful natural scene such as the seashore. A number of paintings feature children and animals with large eyes interacting.