Background: Local anesthetics are commonly used in surgical procedures to control pain in patients. Whilst the cardiotoxicity and neurotoxicity of local anesthetics have received much attention, the cytotoxicity they exert against bone, joint, and muscle tissues has yet to be well recognized.Objective: This review aimed to raise awareness regarding how local anesthetics may cause tissue damage and provide a deeper understanding of the mechanisms of local anesthetic-induced cytotoxicity. We summarized the latest progress on the cytotoxicity of local anesthetics and the underlying mechanisms and discussed potential strategies to reduce it.Findings: We found that the toxic effects of local anesthetics on bone, joint, and muscle tissues were time-and concentration-dependent in vitro. Local anesthetics induced apoptosis, necrosis, and autophagy through specific cellular pathways. Altogether, this review indicates that toxicity of local anesthetics may be avoided by rationally selecting the appropriate anesthetic, limiting the total amount, and determining the lowest effective concentration and duration.