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Antipsychotic-induced weight gain (AIWG) is a pervasive and concerning side effect of treatment with antipsychotic medications (APs) that has grave implications for morbidity and mortality rates in individuals with serious mental illness. As such, acknowledging, identifying, and addressing the metabolic side effects of these medications are critical to improve the overall health and quality of life of individuals treated with APs. This review summarizes the key risk factors and predictors of AIWG and provides a comprehensive and prescriptive overview of the best-researched and evidenced nonpharmacological and pharmacological therapies available to address this problem. Age, prior exposure to APs, and AP type are strong determinants of AIWG. Metabolic monitoring and lifestyle changes remain the methods of choice for addressing metabolic risk in this population. Clinical guidelines have recommended the off-label use of metformin when such interventions are not effective, and there is emerging evidence for the effectiveness of other novel weight loss agents in this population that may represent an opportunity for greater metabolic improvements. Most of the research and guidelines to date have focused on treating AIWG; however, prevention efforts may confer greater benefits given the challenges of reversing weight gain. To effectively mitigate the metabolic risks associated with these medications, substantial system-level reforms in both education and clinical service delivery are essential, with a focus on proactive monitoring and early intervention based on up-to-date evidence and best-practice recommendations.