Merging conceptual and documentary styles, Opie's oeuvre gravitates towards portraiture and landscapes, utilizing serial images and unexpected compositions to both spotlight and blur the lines of gender, community, and place while invoking the formal gravitas reminiscent of Renaissance portraiture and hinting at her deep engagement with the history of art and painting.

The project looked deeper into construction sites, advertisement schemes, homeowner regulations, and the interior layout of their homes within the community of Valencia, California.

[14] Opie and her former partner, painter Julie Burleigh,[15] constructed working studios in the backyard of their home in South Central Los Angeles.

[18] Along with fellow artists John Baldessari, Barbara Kruger, and Ed Ruscha, Opie served as a member of the board for the Museum of Contemporary Art, Los Angeles.

[4] Along with Richard Hawkins, Opie curated a selection of work by the late artist Tony Greene at the 2014 Whitney Biennial, in New York.

[22] Opie's work is characterized by a combination of formal concerns, a variety of printing technologies, references to art history, and social/political commentary.

These images convey symbolic references to the celebration, embracing, and remembrance of the shift and personal relationship with one's body.

[28] Opie's earlier work relies more heavily on documentary photography as opposed to allegorical, yet still provides a stark relationship to her investigation and use of powerful iconography throughout the years.

[31] Opie has referenced problems of visibility, where the reference to Renaissance paintings in her images declares the individuals as saints or characters.

This series is similar to an earlier work of hers, Domestic (1995–1998), which documented her 2-month RV road trip, portraying lesbian families engaging in everyday household activities across the country.

[34] Drawing inspiration from the transgressive photography of Robert Mapplethorpe, Nan Goldin, and sex radicals, who provided a space for liberals and feminists, Opie has also explored controversial topics and imagery in her work.

[37] Opie's first film, The Modernist (2017), is a tribute to French filmmaker Chris Marker's 1962 classic La Jetée.

[38] Composed of 800 still images, the film features Pig Pen (aka Stosh Fila)—a genderqueer performance artist—as the protagonist.

The Modernist has been described as an ode to the city in which it takes place, Los Angeles, but it is also seen as questioning the legacy of modernism in America.

In 2019, UCLA announced Opie as the university’s inaugural endowed chair in the art department, a position underwritten by a $2-million gift from philanthropists Lynda and Stewart Resnick.