Background: Mas cotek or Ficus deltoidea is conventionally used to treat various diseases and often consumed with other medication and this may give rise to herb–drug interaction. The potential of F. deltoidea for interactions with drug‑metabolizing enzymes of UDP‑gucuronosytranserase (UGT) and glutathione S‑transferase (GST) have not been investigated. Objectives: We had evaluated the potential of methanol, ethanol, and aqueous extracts of F. deltoidea to cause UGT‑ and GST‑mediated herb–drug interaction in vitro. Materials and Methods: The total phenolic content and total phenolic content were determined using modified colorimetric method. In the UGT study, para‑nitrophenol (p‑NP) was employed as a substrate to determine the UGT enzymes activity in rat liver microsomes (RLM) and human liver microsomes (HLM). For the GST study, 1‑chloro‑2,4‑dinitrobenzene was employed as a substrate to determine GST activity in rat liver cytosolic fraction. Results: The total phenolic content in F. deltoidea extracts can be ranked as follows: Methanol extract > aqueous extract > ethanol extract, whereas the content of flavonoid compounds in F. deltoidea extracts can be ranked as: Methanol extract > ethanol extract > aqueous extract. Assessment using the UGT enzymes of RLM (IC50 [Half-maximal inhibitory concentration] = 881.40 ± 1.14 μg/mL) and HLM (IC50 = 63.44 ± 1.20 μg/mL) showed that the methanol extract of F. deltoidea significantly inhibited p‑NP glucuronidation compared with ethanol and aqueous extracts. For GST inhibition study, methanol extract strongly inhibited GST activity (IC50 = 70.73 ± 1.07 μg/mL), whereas no IC50 values were determined for ethanol and aqueous extracts. Conclusion: The methanol extract of F. deltoidea containing the highest flavonoid content highlights the possibility of herb–drug interaction through the modulation of p‑NP UGT and GST activity.