Multiple drug resistance is one of the main problems that hinder successful cancer chemotherapy. Investigations on the development of effective chemotherapeutic agents and drug resistance inhibitors motivate studies on the effects of natural compounds on drug-resistant cancer cells. For this purpose, aqueous, methanol, and ethanol extracts of Fomes fomentarius and Tricholoma anatolicum were prepared. The extracts were evaluated to assess their anticancer and multiple drug resistance modulation activities. Cytotoxic effects of F. fomentarius and T. anatolicum extracts on paclitaxcl and vincristine resistant P-glycoprotein over-expressing MCF-7 cell lines were investigated by cytotoxicity test (XTT). P-glycoprotein reversing ability and MDR modulation effects of the extracts were determined by flow cytomeny through Rhodamine 123 exclusion assay. Furthermore, 11 phenolic compounds in the extracts were characterized by HPLC. As a result of the cytotoxicity assay, IC50 values of the extracts for MCF-7/Vinc were between 1.08 and 1.80 mg/mL, and IC50 values for MCF-7/Pac were found between 1.11 and 2.83 mg/mL. Strikingly, methanol extract of F. fomentalists and ethanol extract of T. anatolicum have potential value to become MDR reversing agents for drug-resistant breast cancer cells.