Fasting hyperglycemia, impaired glucose tolerance, prediabetes, and diabetes are frequently present in patients treated with second-generation antipsychotics (SGAPs) for schizophrenia, bipolar disorder, and other severe mental illnesses. These drugs are known to produce weight gain, which may lead to insulin resistance, glucose intolerance, and metabolic syndrome, which constitute important risk factors for the emergence of diabetes. The aim of this review was to formulate therapeutic guidelines for the management of diabetes in patients treated with SGAPs, based on the association between SGAP-induced weight gain and glucose dysregulation. A systematic search in PubMed from inception to March 2020 for randomized controlled trials (RCTs) of diabetes or prediabetes in patients treated with SGAPs was performed. PubMed was also searched for the most recent clinical practice guidelines of interventions for co-morbid conditions associated with diabetes mellitus (DM) (arterial hypertension and dyslipidemia), lifestyle interventions and switching from high metabolic liability SGAPs to safer SGAPs. The search identified 14 RCTs in patients treated with SGAPs. Drug therapy using metformin as first-line therapy and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or perhaps sodium-glucose cotransporter-2 (SGLT2) inhibitors as add-on therapy, might be preferred in these patients as well, as they favorably influence glucose metabolism and body mass index, and provide cardio-renal benefits in general to the DM population, although for the SGLT-2 inhibitors there are no RCTs in this specific patient category so far. Metformin is also useful for treatment of prediabetes. Arterial hypertension should be treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and statins should be used for correction of dyslipidemia. The outcome of lifestyle-changing interventions has been disappointing. Switching from clozapine, olanzapine, or quetiapine to lower cardiometabolic-risk SGAPs, like aripiprazole, brexpiprazole, cariprazine, lurasidone, or ziprasidone, has been recommended.