Doxorubicin (Dox) is an effective chemotherapeutic agent which is widely used clinically to treat solid tumors. Unfortunately, the use of Dox has been restricted due to serious side effects including skeletal muscle toxicity. The current dogma is that Dox‐induced muscle toxicity (DIMT) is mediated through enhanced oxidative stress, inflammation, and unwanted cell death due to apoptosis and necrosis. We hypothesized that inflammation‐mediated cell death known as “pyroptosis” plays a critical role in DIMT. To test this notion, we generated a mouse model of DIMT where C57BL/6J mice (10±2 weeks, male and female), were treated with Dox [12mg/kg cumulative dose, administered through 3 intraperitoneal (i.p.) injections on alternative days]. Mice were sacrificed 14 days following the last injection of Dox and soleus muscle (SM) was harvested. The expression of TLR4, inflammasome (NLRP3 and ASC), pyroptotic markers (caspase‐1, IL‐1β, and IL‐18), pro‐inflammatory cytokines (TNF‐α and IL‐6), pro‐inflammatory M1 macrophages (iNOS), and anti‐inflammatory M2 macrophages (CD206 and Arginase‐1) were measured using immunostaining and western blot techniques. Skeletal muscle function was measured prior to sacrifice. The results showed a significant increase (p<0.05) in the expression of inflammasome formation, pyroptotic markers, pro‐inflammatory cytokines, and M1 macrophage while a significant decrease (p<0.05) in the infiltration of M2 macrophages was observed following Dox administration as compared to saline treated controls. Furthermore, muscle strength was significantly decreased (p<0.05) in Dox‐treated mice vs. control. These data indicate that Dox induces NLRP3‐ASC inflammasome‐mediated pyroptosis, increases inflammation and M1 macrophage infiltration, while decreasing M2 macrophages thereby causing muscle weakness. We propose that novel strategies specifically targeted towards limiting pyroptosis may help in attenuating DIMT in cancer patients receiving Dox chemotherapy.