Increasing evidence has revealed that microRNAs (miRNAs) are closely associated with multiple myeloma (MM) pathogenesis and progression. Therefore, an in-depth understanding of the biological functions of miRNAs in MM may be helpful for the identification of promising therapeutic techniques for patients with MM. miRNA-765 (miR-765) has been reported to be dysregulated in many types of human cancer. However, the expression pattern, specific roles and underlying mechanisms of miR-765 in MM remain largely unknown. In the present study, plasma miR-765 significantly increased in patients with MM and cell lines. The downregulation of miR-765 in MM cells attenuated proliferation and promoted apoptosis. Bioinformatics analysis predicted that SRY-Box 6 (SOX6) was a putative target of miR-765. This was experimentally verified using a luciferase reporter assay, reverse transcription-quantitative PCR and western blot analysis. Furthermore, plasma SOX6 was downregulated in patients with MM and the downregulation of SOX6 was inversely correlated with that of miR-765 expression. Furthermore, SOX6 knockdown markedly abrogated the effects of miR-765 underexpression on cell proliferation and apoptosis in MM. The current study demonstrated that miR-765 serves an oncogenic role in MM progression by directly targeting SOX6, suggesting that miR-765 may be a potential therapeutic target for MM prevention and treatment.