Lipoic acid is a naturally occurring compound that has been shown to modulate insulin sensitivity when supplemented to the diet. Elevated blood insulin concentrations have been shown to decrease progesterone catabolism in several species by modulating hepatic steroid metabolic enzyme activity and expression. We hypothesized that lipoic acid supplementation would decrease progesterone (P4) catabolism by the liver. Eight ovariectomized ewes were fed an alfalfa-grass ration at 95% of ad libitum for the duration of the experiment. Ewes were randomly assigned to the control group [an empty bolus administered by gavage (n = 4; CON)] or lipoic acid group [supplemented at 32 mg/kg BW administered by gavage (n = 4; LA)]. Progesterone was administered via CIDR devices on day 5 to all ewes. Blood samples were collected daily from day 6 to 9. On day 10, liver biopsies were obtained from each ewe to determine cytochrome P450 2C (CYP2C), cytochrome P450 3A (CYP3A) and aldo-keto reductase 1C (AKR1C) activity. On day 11, serial blood samples were collected after CIDR removal to determine P4 clearance. Ewes treated with LA had a lower rate constant (P < 0.03) for P4 clearance compared to CON ewes; however, no difference (P > 0.05) in hepatic enzyme activity was observed. There was also no difference (P > 0.05) in circulating concentrations of P4 in CON ewes compared to LA ewes on day 6 to 11. We conclude that while lipoic acid decreased P4 clearance from the blood, it did so without affecting hepatic enzyme activity; therefore the mechanism of action is yet to be elucidated.