Metal-on-metal total hip arthroplasty prostheses are known to release cobalt and chrome (CoCr) debris. The local accumulation of these ions and nanoparticles can cause adverse local tissue reaction, which can ultimately determine a negative outcome for patients. The aim of our systematic review was to report the latest evidence on the effects of CoCr particles on local soft tissue with a focus on its clinical relevance. PubMed, Embase, and Cochrane Library databases were screened to perform an extensive review. PRISMA guidelines were applied, and the risk of bias was assessed, as was the methodological quality of the included studies. 27 studies were included after applying the inclusion and exclusion criteria. 3 were human ex vivo studies, 24 were preclinical studies, including 21 in vitro and 3 in animal models. The presence of metal ions results in cell damage by reducing cell viability, inducing DNA damage, and triggering the secretion of cytokines, which are responsible for the inflammatory reaction observed in ALTR. CoCr particles released from MoM implants can cause damage to skeletal muscle, the capsule, and provoke osteolysis and inflammation. The cytotoxic and genotoxic damages, as well as the interaction with the immune system, affect the success of the arthroplasty and lead to a higher rate of revision surgeries. Statement of clinical significance: Ions released from the wear of Metal-on-Metal implant are significantly associated with soft tissue damage, and other local adverse reaction. Multiple mechanistic reasons are proposed.