Clinical trials conducted before drug approval have limitations such as small population size, short duration, controlled settings, and exclusion of vulnerable groups. These constraints prevent the detection of rare, long-term, or population-specific adverse effects. Once a drug enters real-world use, it interacts with diverse patients, comorbidities, and polypharmacy, revealing new risks that require ongoing evaluation. Post-Marketing Surveillance (PMS) ensures continuous monitoring of the benefit–risk bal ance of medicines. This manuscript provides an integrated overview of PMS obligations across major global regulatory authorities including CDSCO (India), USFDA (USA), EMA (Europe), PMDA (Japan), and WHO–UMC (global). Key pharmacovigilance tools—ICSRs, PSURs, PADERs, RMPs, PASS, FAERS, EudraVigilance, VigiBase, and VigiFlow—are summarized to highlight their role in safety signal detection. A comparative regulatory analysis outlines similarities and differences in reporting timelines, early monitoring strate gies, and digital submission systems. Real-world case studies, including Rofecoxib (Vioxx) withdrawal due to cardiovascular risks, the bladder cancer signal associ ated with Pioglitazone, Thalidomide-induced teratogenicity, and Diethylene Glycol contamination in Coldrif syrup, illustrate how PMS systems prevent public health tragedies. Study limitations include restricted access to proprietary internal regulatory data bases and reliance on publicly available electronic sources. The discussion emphasizes strengthening ADR reporting culture, greater use of real-world evidence, and applying digital tech nologies like artificial intelligence for faster signal detection. Overall, the manuscript demonstrates that robust PMS systems are essential for ensuring global drug safety, regulatory compliance, and public trust.