Failure of cancer chemotherapies is often linked to the over expression of ABC efflux transporters like the multidrug resistance P‐glycoprotein (P‐gp). P‐gp expression in cells leads to the elimination of a variety of chemically unrelated, mostly cytotoxic compounds. Administration of chemotherapeutics during therapy frequently selects for cells that over express P‐gp and are therefore capable of robustly exporting diverse compounds, including chemotherapeutics, from the cells. P‐gp thus confers multidrug resistance to a majority of drugs currently available for the treatment of cancers and diseases like HIV/AIDS. The search for P‐gp inhibitors for use as co‐therapeutics to combat multidrug resistances has had little success to date. In a previous study (Brewer et al., Mol Pharmacol 86: 716–726, 2014), we described how ultrahigh throughput computational searches led to the identification of four drug‐like molecules that specifically interfere with the energy harvesting steps of substrate transport and inhibit P‐gp catalyzed ATP hydrolysis in vitro. In the present study, we demonstrate that three of these compounds reversed P‐gp‐mediated multidrug resistance of cultured prostate cancer cells to restore sensitivity comparable to naïve prostate cancer cells to the chemotherapeutic drug, paclitaxel. Potentiation concentrations of the inhibitors were <3 μmol/L. The inhibitors did not exhibit significant toxicity to noncancerous cells at concentrations where they reversed multidrug resistance in cancerous cells. Our results indicate that these compounds with novel mechanisms of P‐gp inhibition are excellent leads for the development of co‐therapeutics for the treatment of multidrug resistances.