The newly protected area in the Ross Sea covers 1.55 million square kilometres (600,000 square miles) of what is among the last remaining stretches of ocean to be unharmed by human activity.
Fishing will be completely banned in 72% of the zone, while limited harvesting of krill and fish will be allowed for scientific purposes in the remainder.
The icy waters are home to penguins, seals, killer whales and mink whales, and are a "last refuge for open-ocean marine life" according to the Antarctic and Southern Ocean Coalition.
They offer a rare window into what marine systems were like "before human exploitation" and are home to a significant proportion of the Antarctic ocean's 10,000 species.
Scientists and campaigners have praised the news, which was the result of work by the Commission for the Conservation of Antarctic Marine Living Resources and the EU.
British endurance swimmer Lewis Pugh, who swam a kilometre in the freezing waters of the ocean, said it "sets a very important precedent" in "one of the most important biodiversity hotspots" on the planet.
"All the freezing swims I undertook in the Ross Sea in 2015 were now absolutely worth it," he said.
He urged the UK government to take a "next step" in conservation by boosting protection in other areas around the Antarctic.
Rod Downie, head of polar for conservation charity WWF, said the move was an important milestone but that there was still a great deal of work to do.
"We are running out of time to get this right, and we also need policy makers to move swiftly on from this success by protecting the Weddell Sea and the Antarcitc Peninsula region, where climate change is most established," he said.
Mr Pugh, along with hundreds of scientists who put their signatures to campaigns for marine protection, is campaigning for the creation of a series of zones which by 2020 would protect an area the size of Australia.