Multiple myeloma (MM) is still an incurable hematologic malignancy. Although new therapeutic strategies have been developed to target different pathways in malignant cells, such as proliferation, differentiation, and apoptosis, better survival rates have also been achieved by the introduction of autologous stem cell transplantation (ASCT). Hematopoietic stem cell transplantation and novel targeted agents, such as proteasome inhibitors, monoclonal antibodies, immunomodulatory drugs, check-point inhibitors and epigenetic modulators, have significantly achieved long remission time and increased survival rates. However, most patients relapse, develop resistance, and eventually die because of refractory disease. All these issues highlight the need to investigate newer therapeutic targets to improve patient outcomes. Natural products play an important role in anti-tumor drug discovery, for this reason, in the investigation of novel natural anti-MM agents, we focused on natural polyphenols. Moreover, plant extracts show no or low toxicity towards normal cells and some of them have also a favorable pharmacokinetic profile. The biological activities of plant extracts are mainly due to their content in polyphenols, flavonoids, and terpenoids. Numerous studies showed that polyphenols, generally recognized as antioxidants, possess anticancer and pro-apoptosis properties. Other studies reported the potential clinical applications of flavonoids for their well-known protective and therapeutic effects against cancer, cardiovascular, and neurodegenerative diseases. The combination of plant extracts with anti-cancer drugs may offer a relevant advantage for therapeutic efficacy by sensitizing malignant cells to drugs and overcoming drug-induced resistance in cancer. For all these reasons, a significant number of polyphenolic compounds isolated from plants are still used nowadays in cancer clinical practice in combination with other drugs, also against hematologic malignancies.