© 2017 Leelarungrayub et al. Objective: The aim of this study was to evaluate the antioxidant and anti-inflammatory activities of Plai oil–encapsulated niosomes (Zingiber cassumunar Roxb.) on inflamed subcutaneous Wistar rat skin by therapeutic ultrasound. Methods: Pure oil from Plai rhizomes was extracted by steam distillation, and antioxidant activities were determined by 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay. Bioactive compounds were analyzed by gas chromatography-mass spectrometry. Niosome particles containing Plai oil were prepared by chloroform film method with sonication before testing for anti-inflammatory activity on locally inflamed subcutaneous rat skin after inducement from lipopolysaccharide with ultrasound once a day for 3 days. Skin temperatures and blood flow were evaluated. Results: Plai oil presented antioxidant activity that inhibited 2,2-diphenyl-1-picrylhydrazyl radicals. Four active compounds found in the essential oil were sabinene, γ-terpinene, terpinene-4-ol, and (E)-1-(3,4-dimethyoxy phenyl) butadiene. Application of ultrasound (0.2 W/cm 2 , 20%, 3 min) with gel containing Plai oil–encapsulated niosomes decreased skin temperature and blood flow to the lowest level compared to the application of neurofen drug or gel-based control. Conclusion: Plai oil, which consists of four main bioactive compounds and possesses antioxidant and anti-inflammatory activities, can be applied against local subcutaneous inflammation when used with therapeutic ultrasound via entrapped niosomes.