The case will now go to the U.S. Court of Appeals for the Fifth Circuit, where the majority of the judges have been appointed by Republican presidents.
Congress slashed the mandate's tax to zero, starting in 2019, as part of its tax-cut bill.
Justice Department lawyers urged the judge to strike down the individual mandate and provisions requiring insurance companies to cover individuals with preexisting health conditions and charge them the same premiums as healthy individuals.
An alliance of 19 Republican attorneys general and a governor led by Texas Attorney General Ken Paxton challenged the law. "Further, the Court declares the remaining provisions of the ACA are INSEVERABLE and therefore INVALID".
He also noted that all nine Supreme Court justices who weighed in on the law said the individual mandate and the pre-existing conditions coverage protections, guaranteed issue and community ratings provisions could not be severed.
Republicans have opposed the 2010 law, the signature domestic policy achievement of President Donald Trump's Democratic predecessor Barack Obama, since its inception and have repeatedly tried and failed to repeal it. Because the mandate is an essential part of the ACA in the judge's view, that led him to rule that the entire health law should be struck down.
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In oral arguments in September, a lawyer for California said that the harm from striking down the law would be "devastating" and that more than 20 million Americans were able to gain health insurance under it.
"When House Democrats take the gavel, the House of Representatives will move swiftly to formally intervene in the appeals process to uphold the life-saving protections for people with pre-existing conditions and reject Republicans' effort to destroy the Affordable Care Act", Mrs. Pelosi said. They don't need their own health insurance.
Information cards displayed during an Affordable Care Act enrollment event in San Antonio, Texas, in 2016.
"Obamacare has been struck down by a highly respected judge", White House press secretary Sarah Sanders said in a statement. The lawsuit argues that, with the enforcement of the insurance requirement gone, there is no longer a tax, so the law is not constitutional anymore. "We want to make sure that people with pre-existing conditions have protection, and we want to make sure that people have access to affordable coverage".
Legal expert Timothy Jost, a supporter of the health law, said O'Connor's ruling would have repercussions for almost all Americans if it stands.
But other states have argued that eliminating Obamacare would harm millions of Americans, and pending any appeal the landmark health care law remains in place.