Unsaponifiable fractions (USF) derived from palm oil fatty acid distillate (PFAD) are rich in diverse bioactive constituents, such as tocopherols, tocotrienols, phytosterols, and β-carotene. These fractions offer promising applications as dietary supplements due to their antioxidant, anti-inflammatory, and cholesterol-lowering properties, which may benefit various diseases and metabolic disorders. However, a significant limitation of USF is its poor solubility in water. This research addresses the challenge of USF’s low aqueous solubility by employing a self-nanoemulsification technique, utilizing two surfactants, Tween 80 and sodium stearoyl lactylate (SSL), at concentrations of 5, 10, and 15% based on oil phase. Bioactivity was assessed using an HMGCoA Reductase (HMGR) assay kit. The resulting nanoemulsions exhibited particle sizes ranging from 55 to 162 nm, with the smallest size observed in formulations containing 15% Tween 80. Tocotrienols and phytosterols were identified as the predominant phytochemicals in the nanoemulsions. HMGR activity was lower in the nanoemulsions compared to PFAD, USF, and statin-class HMGR inhibitors. Notably, nanoemulsions formulated with Tween 80 demonstrated lower specific activity than those with SSL, likely due to differences in their molecular structures and interfacial behaviors.