A rapid and efficient method for the simultaneous detection of lignans (sesamol, sesamin, sesamolin) and tocopherols (α-tocopherol, γ-tocopherol, δ-tocopherol) in sesame oil by reversed-phase high-performance liquid chromatography (RP-HPLC) has been established. The samples were ultrasonically extracted in methanol and eluted via a methanol-water gradient on a reversed-phase C18 column with UV/Vis detection. The recoveries of the six analytes ranged from 88.22% to 100.13%, and the relative standard deviations (RSD, n = 6) ranged from 1.90% to 4.57%. This method allowed for measurement of the concentrations of lignans and tocopherols in six commercial sesame oils. This technique is simple, accurate, and highly sensitive and can therefore be used for the routine analysis of real samples.