A pop-up security barrier stopped the car with an Arkansas licence plate at the Oconee Nuclear Station near Seneca about 8pm on Thursday, Oconee County Sheriff's spokesman Jimmy Watt said in a statement.
The driver backed up and tried to drive down a dirt road as Duke Energy security tried to block him in.
The driver tried to hit the guards, then drove through a fence and off the nuclear plant property, Watt said.
He drove a short distance from the plant and shots were fired, although deputies haven't determined who fired them, Watt said.
The same car showed up an hour before trying to crash through the gate and the driver was asked to leave, deputies said.
A bulletin was issued to police across the US to look for a silver 2002 Toyota Camry with an Arkansas tag 380-VDR, Watt said.
None of the security staff was injured, Duke Energy said.
The Oconee Nuclear Station has three nuclear reactors and started generating power 50 years ago on Lake Keowee.
The plant continues to operate safely, officials said.
"Duke Energy has comprehensive security plans and a well-trained security workforce in place. A vehicle entered an administrative gate but was not able to access the plant due to our multiple layers of security," Duke Energy said in statement.
