Sweet potato leaves (SPL) are a valuable source of phytonutrients with nutritional and various health-promoting benefits. This study evaluated the effects of green and purple SPL supplementation on hepatic xenobiotic-metabolizing enzymes (XME) and membrane transporters, and benzo[a]pyrene (B[a]P) metabolism and B[a]P accumulation in rats. The experiments were conducted in standard and B[a]P-treated rat models. The first experiment showed that rats fed a diet containing 5% (w/w) green or purple SPL for two weeks showed increased hepatic activity of cytochrome P-450 (CYP)1A1/1A2 and glutathione S-transferase. Green SPL supplementation also increased the CYP2C, CYP2D and CYP3A and multidrug resistance-associated protein 2 levels in the liver. Notably, green and purple SPL induced nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 protein expression and reduced oxidative stress in the liver. The second experiment was to evaluate the effects of green and purple SPL supplementation on B[a]P metabolism and B[a]P accumulation in rats. Rats were fed SPL diets (the same as experiment I) for two weeks. When rats were exposed to a single dose (25 mg per kg BW) of B[a]P, green SPL had no effect on B[a]P-induced elevation of CYP1A1 activity but induced GST activity in the intestinal mucosa and the liver. Green SPL also increased hepatic UDP-glucuronosyltransferase activity and reduced B[a]P levels in the plasma, liver, and intestinal mucosa. A lower plasma 8-hydroxy-2'-deoxyguanosine level was found after B[a]P treatment only in the green SPL group. This study suggests that, in the standard rat model, green and purple SPL may increase Nrf2-mediated antioxidant activity and facilitate the xenobiotic detoxification process by increasing hepatic XME and transporters. When exposed to B[a]P, however, only green SPL consumption may increase hepatic B[a]P metabolism and lower the B[a]P level in the liver by increasing phase II detoxifying enzyme activities.