Persistent organic pollutants (POPs) may alter tumor cells phenotype, possibly increasing malignancy, but there is a lack of studies investigating the mechanisms by which POPs may affect tumor cells. The ATP-Binding Cassette (ABC) transporter proteins are a widely studied component of drug resistance and tumor progression. We hypothesized that the levels of BDE-209 and TCDD detected in human serum can modulate the gene expression or activity of ATP-binding cassette (ABC) transporters in murine melanoma (B16-F1) cells. In this study, we observed an upregulation of the ABCB1 and ABCC4 (24 h) genes followed by an increased protein activity after BDE-209 15 day-exposure. We also observed that cells exposed to TCDD showed an upregulation of ABCB5, ABCC1 and ABCC4 genes (24 h) and change of protein activity after 15 days of exposure. These findings suggest that BDE-209 and TCDD can regulate the phenotype of B16-F1 cells by interfering with the expression and activity of ATP-binding cassette (ABC) transporters. This investigation revealed that environmental pollutants might intervene and modify cells’ resistance to chemotherapy and cancer prognosis.