The pair have previously worked together on MacFarlane's 2014 big-screen western comedy "A Million Ways to Die in the West", reported Entertainment Weekly.
The hour-long Fox series takes place several hundred years from now and chronicles the exploits of the USS starship The Orville, which is captained by Ed Mercer (MacFarlane).
Details of Theron's character are being kept under wraps.
The episode will air sometime this autumn.
Theron's last episodic TV appearance was a 2005 cameo on "Arrested Development".
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