The Department of Justice has sued Mr Lowe and his wife Lauren, alleging "recurring inhumane treatment and improper handling" of tigers and lions.
Mr Lowe hasn't commented but has previously accused the government of making "false accusations" against him.
He took over the Oklahoma zoo from his ex-business partner Joe Exotic in 2016.
Greater Wynnewood Exotic Animal Park, which housed more than 230 tigers and lions, has been targeted in a series of inspections by the United States Department of Agriculture (USDA).
Mr Lowe has said the agency had bowed to pressure from animal rights charity Peta, and that his park had become a target for "every nutjob and animal rights loon in the world".
On Thursday, the Department of Justice (DoJ) said it had filed a civil lawsuit against Mr and Mrs Lowe, accusing them of "illegally taking, possessing, and transporting protected animals" including a grizzly bear and ring-tailed lemurs as well as tigers and lions, and "placing the health of animals in serious danger".