California Department of Health Care Services Director Jennifer Kent called the proposal a "sledgehammer" to the state’s health care system.
“It cannot be understated about how significant the cuts would be to a state that has relied on that 50-plus year relationship going forward," Kent told reporters on a conference call.
Medi-Cal Director Mari Cantwell said the state could be forced to make deep cuts to enrollment, services and provider fees.
Additional options would include taking money from other parts of the budget.
The GOP plan in the U.S. Senate dramatically slows spending on Medicaid and shifts much of the federal costs to states.
"This is significantly more problematic for California than the House bill. Although the House bill in and of itself was terribly devastating, this expands on that," Cantwell added.
California added nearly four million people to its program under the recent Medicaid expansion.
Altogether, more than 13 million Californians are enrolled in Medi-Cal, which is a partnership between the state and the federal government.
Republican senators this week delayed a vote on the federal bill until after the July 4th holiday.