BACKGROUND: Calreticulin (CALR) has been implicated in the genesis and progression of numerous tumors. Nevertheless, its impact on multiple myeloma (MM) remains ambiguous. This study aimed to explore the effect of CALR on the proliferation and drug sensitivity of MM cells and to delve into its underlying mechanism. METHODS: First, the expression of CALR in MM cells was measured. Subsequently, the impact of CALR knockdown on MM cells was validated both in vitro and in vivo. Finally, RNA sequencing was utilized to explore the molecular mechanisms associated with CALR knockdown. RESULTS: We determined that CALR is upregulated in myeloma cells. Both in vitro and in vivo functional assays demonstrated that CALR knockdown attenuated the proliferative capacity of MM cells, heightened their sensitivity to bortezomib (BTZ), and facilitated MM cell apoptosis. RNA-sequencing results indicated that CALR knockdown activates the apoptosis pathway, with the underlying mechanism potentially involving the regulation of the BCL2 signaling pathway. CONCLUSION: This study indicates that CALR is associated with the proliferation and drug sensitivity of MM. Targeting CALR might be a potential strategy to further enhance the treatment efficacy for MM. CLINICAL TRIAL NUMBER: Not applicable.