Background: In order to develop oil palm empty fruit bunch (EFB) lignin as a nutraceutical and health supplement, the investigation of its potential in interacting with other drugs via inhibition of drug-metabolizing enzymes (DMEs) would ensure product safety. Objective: The study was aimed to investigate the in vitro effect of oil palm EFB lignin and its main oxidation compounds on phase II DME UDP-glucuronosyltransferases (UGTs) in rat liver and kidney microsomes. Materials and Methods: The p-nitrophenol (p-NP) and 4-methylumbelliferone (4-MU) were employed as probe substrates in glucuronidation assays. The effect of soda oil palm EFB lignin on Vmax, Km, CLint, Ki, and mode of inhibition of 4-MU glucuronidation in RLM was also determined. Results: The inhibitory potency of oil palm EFB lignin for both p-NP and 4-MU glucuronidation in rat liver microsome (RLM) and rat kidneys microsomes (RKM) was found to be in the rank order of soda > kraft > organosolv. However, the inhibitory potency of its main oxidation compounds were in the rank order of vanillin > syringaldehyde > p-hydroxybenzaldehyde. Soda oil palm EFB lignin exhibited mixed-type inhibition against 4-MU glucuronidation in RLM, showing the change in apparent Vmax and with only a minor effect on Km compared with control. Conclusions: The findings showed that effect of oil palm EFB lignin on both p-NP and 4-MU glucuronidation in RLM and RKM was enhanced by the presence of vanillin as well as flavonoids. Kinetic study showed that soda oil palm EFB lignin exhibited strong inhibition on UGT activity in RLM with mixed-type inhibition mode.