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Cancer recurrence, which is frequently accompanied by chemotherapy, has been a challenge in cancer treatment. This study was carried out to examine the potential applications of the reactive oxygen species (ROS)-producing cold atmospheric plasma (CAP) to overcome the cancer cells’ drug resistance, which has been emerging as an alternative therapeutic tool for cancer. For this, we developed a tamoxifen (Tam)-resistant MCF-7 (MCF-7/TamR) breast cancer cell model and examined the effect of CAP on the recovery of Tam sensitivity at the cellular and molecular level. The ROS level was increased 1.9-fold in CAP-treated MCF-7/TamR cells compared to the non-treated cell. CAP was proven to restore sensitivity by up to 50% for MCF-7/TamR cells against Tam after CAP treatment. The comparison of genome-wide expression between the acquisition of Tam resistance and CAP treatment identified 20 genes that commonly showed significant expression changes. Notably, all the genes except two have been oppositely dysregulated in the two cellular statuses, and the majority of them are known to contribute to the acquisition of Tam resistance. The protein expression of selected genes, MX1 and HOXC6, was recovered to that of their parental cell by CAP. Furthermore, the dysregulation of MX1 and HOXC6 in MCF-7/TamR alleviated the drug sensitivity recovery effect of CAP. Taken together, CAP inhibited the growth of Tam-resistant MCF-7 cancer cells and reset it to the Tam-sensitive status by restoring the expression of drug resistance–related genes. These findings may lend credence to CAP as an alternative or complementary tool in the treatment or prevention of Tam-resistant cancer.ROS is increased in the cold atmospheric plasma-treated tamoxifen-resistant MCF-7.Cold atmospheric plasma sets the drug-resistant MCF-7 back to the sensitive status.Tamoxifen resistant-related genes are restored by cold atmospheric plasma.Dysregulation of MX1 and HOXC6 alleviates the effect of cold atmospheric plasma.