| Summary: | <i>Capsicum chinense</i> J., also known locally as habanero pepper, is a medicinal herb known for its pharmacological properties. Its properties are attributed to the capsaicinoids and polyphenols found in its fruit and polyphenols in its by-products. The anticancer potential of <i>C. chinense</i> by-products remains unexplored. This study aimed to evaluate the antiproliferative activity and modulation of the cytotoxicity of extracts obtained from <i>C. chinense</i> by-products of plants grown on black and red soils of Yucatan, Mexico. Dry by-product extracts were obtained using maceration, a Soxhlet, and supercritical fluid extraction. In vitro antiproliferative activity and cytotoxicity modulation were evaluated by the sulforhodamine B method. The extract of leaves of plants grown on black soil obtained by maceration displayed selective high cytotoxicity against colorectal cancer cells, IC<sub>50</sub> HCT–15 = 16.23 ± 2.89 µg mL<sup>−1</sup>. The leaf and stem extracts of plants grown on red soil obtained by maceration potentiated the vinblastine’s effect against parental breast cancer cells, MCF–7/Sens, with a reversion factor of 362.50-fold. Additionally, the extract of stems from plants grown on black soil obtained by supercritical fluid extraction and all the by-product extracts from plants grown on black soil obtained through maceration increased the effect of vinblastine against MCF–7/Vin<sup>+</sup> with a reversion factor from 5.06- to 7.78-fold. These results highlight the anticancer potential of <i>C. chinense</i> by-products.
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