The central idea of the story resides in the confusing relationship between art and life. In "The Oval Portrait", art and the addiction to it are ultimately depicted as killers, responsible for the young bride's death. In this context, one can synonymously equate art with death, whereas the relationship between art and life is consequently considered as a rivalry. It takes Poe's theory that poetry as art is the rhythmical creation of beauty, and that the most poetical topic in the world is the death of a beautiful woman (see "The Philosophy of Composition").

"The Oval Portrait" was first published as a longer version titled "Life in Death" in Graham's Magazine in 1842. "Life in Death" included a few introductory paragraphs explaining how the narrator had been wounded, and that he had eaten opium to relieve the pain. Poe probably excised this introduction because it was not particularly relevant, and it also gave the impression that the story was nothing more than a hallucination. The shorter version, renamed "The Oval Portrait", was published in the April 26, 1845 edition of the Broadway Journal.

The story inspired elements in the 1891 novel The Picture of Dorian Gray by Oscar Wilde. Five years before the novel's publication, Wilde had praised Poe's rhythmical expression. In Wilde's novel, the portrait gradually reveals the evil of its subject rather than that of its artist.

A similar plot is also used in Nathaniel Hawthorne's 1843 tale "The Birth-Mark".

There are similar elements in "The Fall of the House of Usher", such as a painter, his lover/model in a remote setting and especially their obsessions about inanimate objects that are living (the house in "The Fall of the House of Usher" and the painting in "The Oval Portrait"). In 1928, a French film-maker, Jean Epstein, filmed La Chute de la Maison Usher which combined both stories. Artist Richard Corben combined them in his 2012 adaptation after adapting each on their own.

Lance Tait's 2002 play The Oval Portrait is based on Poe's tale. Laura Grace Pattillo wrote in The Edgar Allan Poe Review (2006),

[Tait] takes Poe’s narrative and intriguingly transforms it into a dialogue between the Model and the Portrait. The mood of the piece is a bit different from the original Poe work, and it is unclear at the end whether the Model will actually die (literally or figuratively) as in Poe's tale but Tait is to be commended for creating dialogue that makes Poe’s tale come alive beyond the narrative limitations of the original prose.