Breast cancer (BCa) is one of the leading causes of cancer-related death among women worldwide. At present, the clinical treatment with tamoxifen (TAM) is challenged by the development of drug resistance. To investigate the effect of corylin on TAM resistance in BCa cells, this study investigated the molecular mechanisms involving miRNA-mRNA targets modulated by corylin. The TAM-resistant MCF-7TR and T47DTR cell lines were generated, and it was found that corylin treatment reduced the cell viability of these cells significantly. Furthermore, OAS1 was validated to be highly expressed in TAM-resistant cells, while OAS1 knockdown sensitized MCF-7TR and T47DTR cells to TAM treatment. Meanwhile, OAS1 was also repressed by corylin treatment, indicating that OAS1 was a key regulator of corylin function. Through bioinformatic analysis, the tumor suppressive miRNA miR-22-3p was identified to directly target and inhibit OAS1. Moreover, corylin treatment up-regulated miR-22-3p expression, which thus down-regulated the OAS1 expression. Interestingly, OAS1 itself functioned as a miR-22-3p sponge to repress miR-22-3p expression. Further, SIRT1 was identified to be up-regulated in TAM-resistant cells and participated in the OAS1/miR-22-3p regulatory axis via the miR-22-3p direct target. In conclusion, corylin sensitized TAM-resistant cells to TAM treatment by inhibiting OAS1 expression and modulating the OAS1/miR-22-3p/SIRT1 axis.