<p>To analyze reporting trend, character and factors associated with serious adverse events (SAEs) following sodium-glucose co-transporter 2 inhibitors (SGLT2i) therapy in the FAERS database and detect pharmacovigilance signals. Standardized data were subjected to descriptive analysis. Odds ratio (OR) with 95% confidence interval (CI) was calculated to identify associated factors. Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR) and 95% lower credibility interval of Information Component (IC₀₂₅) were used to detect signals. 28709 reports (45%) were identified as SAE reports with SGLT2i as primary suspect. Hospitalization (66.86%) and death (20.21%) were major contributors. Dapagliflozin and empagliflozin accounted for more than 70% SAE reports, followed by canagliflozin (26.63%). Male gender (OR = 1.4, 95% CI = 1.35–1.45), age more than 65 years (OR = 1.72, 95% CI = 1.66–1.79) and canagliflozin (OR = 2.05, 95% CI = 1.94–2.16) were identified as factors associated with SAE. Dapagliflozin was associated with death (adjusted OR = 5.22, 95% CI = 4.77–5.72), while canagliflozin had the highest association with hospitalization (adjusted OR = 2.65, 95% CI = 2.52–2.79). 435 signals were detected of which 112 were strong signals (IC₀₂₅ &gt; 4). Fournier’s gangrene (N_PS = 1152, IC = 6.84), acute osteomyelitis (175, 6.59), limb amputation (129, 6.79), metatarsal excision (81, 6.79) and euglycemic diabetic ketoacidosis (1485, 6.75) were top signals. Cellulitis, acute pancreatitis and necrotizing pancreatitis were unexpected signals with SGLT2i. <b>Conclusion:</b> SAE reports contributed to a large proportion of reports with SGLT2i in the FAERS database. SAE profile of individual SGLT2i varied.</p>