Perilla frutescens var. crispa (Pfc) of the family Lamiaceae is used as a medicinal plant due to its pharmacological properties. Although Pfc is an important resource for the medical nutrition industry, the variability in phytonutrients and biological activities among genotypes of Pfc is not well understood. The effects of genotype on the phytochemical composition, antioxidant activities, antimelanogenic principles, and anti-inflammatory effects of Pfc were determined using eight Pfc genotypes. Using HPLC analysis, we identified 30 polyphenolic compounds from Pfc, although variation was observed in the polyphenolic composition of Pfc genotypes. Pfc 5 exhibited antimelanogenic activity in B16F10 melanoma cells via inhibition of tyrosinase activity. In addition, Pfc 2 strongly inhibited lipopolysaccharide-induced nitric oxide production through translational downregulation of inducible NOS in RAW264 murine macrophages. Taken together, the results of our study reveal the significant impacts of genotype on phytonutrients and biological activities. This finding will assist in the breeding and genetic engineering of Pfc in order to meet future phytonutrition and health challenges.