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Electrochemotherapy is a minimally invasive treatment based on the principle of reversible electroporation of target cells in pathologic tissues in order to increase the local effect of chemotherapeutic agents. The mechanism of action relies on temporarily increasing cell permeability to increase the uptake of cytotoxic drugs in the intracellular space. Originally developed for the treatment of cutaneous malignancies, electrochemotherapy has significantly evolved over the past few decades, thanks to advancements in electrode design and image guidance, finding fertile ground in musculoskeletal oncological pathologies, such as bone and soft tissue tumors and different kinds of vascular malformations. Moreover, initial experiences have reported on the treatment of other soft tissue tumors such as desmoid fibromatosis. The aim of this review is to summarize the literature on the role of electrochemotherapy across a variety of musculoskeletal conditions, starting from established oncologic indications, such as metastatic bone or soft tissue tumors, to emerging evidence on primary musculoskeletal pathology, with particular attention paid to the results of the leading studies relating to the efficacy, complications, and recurrence rate.