A GC-MS method was developed for the determination of various flavonoids and phenolic and benzoic acids in human plasma. The procedure involved the extraction of flavonoids and phenolic and benzoic acids with ethyl acetate, followed by the derivatization of the phenolic and benzoic compounds with BSTFA (N,O-bis(trimethylsilyl) trifluoroacetamide) + TMCS (trimethylchlorosilane) reagent. The trimethylsilyl derivatives formed were separated and quantitated using GC-MS. Twenty flavonoids and phenolic and benzoic compounds have been well separated in the spiked human plasma without any interference. The average recovery was 79.3%. Several phenolic acids such as o-hydroxybenzoic, p-hydroxyphenylacetic, 2,3-dihydroxybenzoic, 2,4-dihydroxybenzoic, ferulic, sinapic, and benzoic acid were identified and quantified in human plasma after consumption of a cranberry juice. This developed method provides a simple, specific, and sensitive technique for the simultaneous determination of flavonoids and phenolic and benzoic acids in human plasma and is suitable for bioavailability and pharmacokinetic studies.