Tamoxifen therapy stands as a cornerstone in the treatment regimen for estrogen receptor positive breast cancer. However, emergence and management of tamoxifen resistance pose significant clinical hurdles. Hence, comprehending intricate molecular mechanisms of tamoxifen resistance becomes imperative. This study endeavors to decipher molecular mechanisms underlying acquired tamoxifen resistance. Integrated meta-analysis approach was employed on available microarray gene expression datasets to identify potential targets implicated in tamoxifen resistance. In silico findings were experimentally validated using MCF-7TamR cells model. Meta-analysis highlighted involvement of inflammatory pathways mainly up-regulation of chemokines in tamoxifen resistant breast cancer cells compared to control. qPCR analysis further confirmed significant up-regulation of chemokine genes, including CCL2, CCL20, CXCL6, CXCL14, CXCL12, CXCR4, CCR5, and CCL3 in MCF-7TamR cells. To delineate specific roles of these chemokines in tamoxifen resistance, MCF-7TamR cells were subjected, to selected inflammatory/chemokine antagonists, separately. The observed attenuation of cellular growth, induction of DNA damage, apoptosis, and cell cycle arrest, coupled with the down-regulation of chemokine gene expression, suggests a reversal of the resistance phenotype in treated cells compared to untreated resistant cells. In conclusion, our findings propose that inflammatory chemokines hold the potential to reverse tamoxifen resistance and augment drug sensitivity, offering a promising avenue for mitigating and overcoming tamoxifen resistance in breast cancer therapy.