Abstract: Objective To mine risk signals of drug-induced hypophosphatemia, summarize potential high-risk medications, and provide references and warnings for safe clinical medication. Methods Based on four distinct types of real-world databases, disproportionality analysis and Bayesian analysis were combined to detect the signal strength of hypophosphatemia. Drugs meeting all algorithmic thresholds were defined as valid study drugs, and the demographic characteristics, onset time, and patient outcomes of these drugs were further analyzed. Results A total of 131 valid study drugs with hypophosphatemia risk signals were identified, involving 7,846 case reports. Among them, 33 drugs (25.19%) represented novel pharmacovigilance signals. In terms of drug classification, antineoplastic and immunomodulating agents accounted for the highest proportion (48.09%), followed by systemic anti-infectives (17.56%). Demographically, middle-aged and young adults (18-59 years) constituted a large share, with a male-to-female reporting ratio of 100:143. Drugs with the strongest signal strengths included dialysis solutions, adefovir dipivoxil, ferric carboxymaltose, burosumab, oxcarbazepine, and nirogacestat. Regarding onset time, the median time for most antineoplastic drugs was less than 30 days. For clinical outcomes, 50.24% of reports were classified as serious adverse outcomes; the top five drugs with the highest proportion of death reports were zoledronic acid, sorafenib, denosumab, everolimus, and bevacizumab. Conclusions Clinical attention should be focused on drugs without documented hypophosphatemia risks in their package inserts, and enhanced monitoring is recommended for high-risk populations including young and middle-aged individuals, women, and cancer patients. In clinical practice, it is recommended to implement stratified monitoring based on drug risk signals, and to take timely interventions-such as drug withdrawal, substitution, electrolyte supplementation, and hydration-with the aim of effectively correcting hypophosphatemia.