Human melanoma cells are known as one of the most aggressive cancer cells, and consequently, melanoma is one of the most incurable cancer diseases. There is intense activity in research and development of potential medicines for malignant diseases, including alternative forms of remedies. Therefore, the purpose of our work was testing extracts from the common houseleek (Sempervivum tectorum) grown in Slovenia to establish its impact on human melanoma cells. Namely, we wanted to verify if the extracts inhibit growth of malignant cells and their metabolic activity. Soxhlet, cold solvent, ultrasound, and supercritical extraction methods were applied to obtain S. tectorum extracts. Polyphenols and proanthocyanins content in acquired extracts was determined as well as their antioxidative potential. For a relevant comparison, Chinese (CHI) dried and Slovenian (SLO) lyophilized S. tectorum was used. Results showed that the highest contents of polyphenols and proanthocyanins were yielded from lyophilized material, which also had the highest antioxidative potential. The focus of our work was on analysis of possible inhibition effects of the extracts on human melanoma cells since no past studies were found regarding the possible effects of S. tectorum on metabolic activity of WM-266-4. We established that in a 24-h incubation period, the extracts inhibited metabolic activity of the cells at their concentrations of 20, 10, 4, 2, 1, 0.2, and 0.02 mg/mL. Extract obtained from SLO S. tectorum (ultrasound extraction with acetone as a solvent), which showed promising results of inhibitory effect on the mentioned cells, was further described since the local plant was the focus of our study. CHI S. tectorum extract (Soxhlet extraction with ehtanol:water mixture = 1:1 as a solvent) showed the highest inhibitory effect on human melanoma cells WM-266-4, although both obtained extracts are suitable for their growth inhibition of this specific cell line. Our results suggest inhibitory ability of S. tectorum extracts on the metabolic activity of WM-266-4 metastatic cell line, suggesting their potential use as an anticancer agent.