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Background: Exosomes are extracellular vesicles released by cells that mediate intercellular communication and actively participate in cancer progression, metastasis, and regulation of immune response within the tumour microenvironment. Inhibiting exosome release from cancer cells could be employed as a therapeutic against cancer. Methods and results: In the present study, we have studied the effects of Acorus calamus in inhibiting exosome secretion via targetting Rab27a and neutral sphingomyelinase 2 (nSMase2) in HER2-positive (MDA-MB-453), hormone receptor-positive (MCF-7) and triple-negative breast cancer (MDA-MB-231) cells. We observed that treatment with A. calamus significantly downregulated the expression of Rab27a and nSMase2 in all tested cells. NTA analysis showed that inhibition of Rab27a and nSMase2 reduced exosome secretion from breast cancer cells. We conducted metabolic profiling of A. calamus extract to reveal the phytochemicals present and docked them on Rab27a and nSMase2 to decipher the compounds responsible for protein inhibition. Molecular dynamic simulations were conducted on lead compounds, and we observed that calcitriol lactone showed the most stable binding interactions with nSMase2. Treatment of breast cancer cells with calcitriol lactone significantly downregulated nSMase2 expression. Conclusions: Our study demonstrates that A. calamus significantly inhibits exosome secretion in HER2-positive, hormone receptor-positive, and triple-negative breast cancer cells by targeting key regulatory proteins Rab27a and neutral sphingomyelinase 2 (nSMase2). These findings suggest that A. calamus holds therapeutic potential in inhibiting exosome-mediated cancer progression by targeting the exosome secretion pathway. Further investigations are warranted to explore the clinical applications of these findings in breast cancer treatment. [ABSTRACT FROM AUTHOR]