Hyperpigmentation causes patches of skin to blemish and may lead to serious skin disorders. Prevention of hyperpigmentation would require suppressing the melanogenesis pathway which uses the rate limiting enzyme tyrosinase. South African plant extracts, Myrsine pillansii, Rapanea melanophloeos, Vachellia karroo, Kalanchoe thyrsiflora, Ormocarpum trichocarpum and Myrsine africana were tested for their tyrosinase inhibiting potential at both the tyrosinase activity and tyrosinase gene expression levels. The plant extracts, O. trichocarpum and V.karroo, have the most effective inhibition of 50% of the tyrosinase enzyme at concentrations of 2.95 and 6.84 μg/ml, respectively. The cytotoxicity of the plant extracts were investigated using B16-F10 mouse melanocyte cells. The tyrosinase gene expression levels were examined on the B16-F10 mouse melanocyte cells treated with the South African plant extracts, through real-time reverse transcription polymerase chain reaction (RT-qPCR). Three of the mouse melanocyte samples treated with K.thyrsiflora, M. pillansii and V.karroo showed significant down regulation of tyrosinase gene expression (p-value < 0.05) at 1.2, 3.7 and 12.7 fold, respectively. These plant extracts indicate depigmenting potential through inhibition of tyrosinase directly and at the transcriptional level and therefore, should be investigated further.