The Snail family transcriptional repressor 1 gene (Snail1) was screened in multiple myeloma cells (MMCs) from bortezomib-resistant MM patients and was found to be significantly associated with the development of drug-resistance mechanisms. In the present study, we first confirmed that the protein expression of Snail1 in bortezomib-resistant MMCs was significantly higher than that in MMCs without bortezomib resistance. The mechanistic studies confirmed that the enhancement of Snail1 expression in bortezomib-resistant MMCs directly upregulated transcription of the intracellular MDR1 gene to immediately develop multiple drug resistance mechanisms and inhibited P53 protein expression through the Snail1/hsa-miRNA-22-3p/P53 pathway to inhibit tumor cell apoptosis. By upregulating MDR1 and downregulating P53, Snail1 induced the drug resistance of MMCs to bortezomib, while Snail1 gene silencing effectively improved the drug sensitivity of MMCs to bortezomib chemotherapy. The present study further elucidated the drug resistance mechanisms of MMCs and provides evidence for increased clinical efficacy of bortezomib in MM patients.