Multiple myeloma (MM) is the second most common hematological tumor characterized by the proliferation of monoclonal plasma cells. Melphalan (MEL) is commonly used in the treatment of MM and is especially essential for patients undergoing autologous stem cell transplantation (ASCT). Although many drugs for MM have been developed in recent years, chemotherapy followed by ASCT remains the optimal option. Melphalan, the backbone of the conditioning regimen, brings severe toxicities at a high dose. Nanodrug delivery systems enable drugs to be highly effective and have low toxicity. In this study, methoxy poly(ethylene glycol)-poly(d,l-lactide) copolymer (MPEG-PDLLA) was chosen to encapsulate melphalan, and the characteristics, effectiveness, and safety of MEL/MPEG-PDLLA in vitro and in vivo were investigated. MEL/MPEG-PDLLA showed slow release and was easily engulfed by MM cells despite a result of the antitumor assay comparable to that of free melphalan in vitro. The in vivo results showed that MEL/MPEG-PDLLA could significantly alleviate tumor burden and prolong survival time without increasing the toxicity to vital organs. In addition, MEL/MPEG-PDLLA could significantly reduce the damage to the intestinal mucosa caused by melphalan. In conclusion, MEL/MPEG-PDLLA shows improved antitumor activity and has the potential to alleviate pains of MM patients undergoing ASCT.