The channel launched on February 1, 2000, under the ownership of Oxygen Media, a consortium including Geraldine Laybourne and Oprah Winfrey among other stakeholders.

Oxygen Media was acquired by NBC Universal in 2007 for nearly $1 billion, after which the channel began to place a stronger focus on targeting young adult women.

[3] Oxygen's operations were later consolidated at Chelsea Market, a former Nabisco factory at 15th Street and Ninth Avenue in New York City.

[4] Prior to 2005, the channel carried a limited schedule of regular season WNBA games produced by NBA TV.

NBCU cable head Jeff Gaspin stated that Oxygen would be marketed to advertisers alongside sister properties targeting an "upscale" female audience, such as Bravo, iVillage, and Today.

Some of Oxygen's executives departed during the integration, with Laybourne and president of programming Debby Beece both stepping down, and Gersh transitioning to roles at other NBCU divisions (including The Weather Channel, and later NBC News).

With a Bad Girls Club: Atlanta reunion special as a lead-in (which drew a series high of nearly 2 million viewers), Nielsen estimated that Oxygen had achieved its highest-rated night of key demographic viewership to-date, and the top two programs on cable that evening.

Berwick explained that the new slate, which included upcoming series such as Fix My Choir, Funny Girls, Nail'd It, Sisterhood of Hip Hop, Street Art Throwdown, and planned spin-offs of Preachers of L.A., would "deliver on the freshness, authenticity, high emotional stakes and optimism that this demographic is looking for", and that many of the new programs would "appeal to things that are important in the lives of young, millennial women" and be "authentic".

[19] NBCUniversal had reportedly been in talks with Dick Wolf—producer of NBC's Law & Order and Chicago franchises—to take an equity stake in a re-branded channel that could be led by reruns of the programs.

[23][24] Oxygen's new lineup was built largely around its existing library of unscripted true-crime programming (such as Snapped), and reruns of police procedurals such as the CSI and NCIS franchises.

The channel launched on January 1, 2025, replacing the similarly-formatted Oxygen competitor Investigation Discovery, following Bell's loss of rights to Warner Bros.