Adverse drug reactions (ADRs) remain a major, yet largely preventable, global public health challenge, causing significant morbidity, mortality, and healthcare costs. This review synthesises evidence on the global burden, pharmacovigilance systems, and prevention strategies for ADRs, integrating data from multiple regions, healthcare settings, and drug classes. Epidemiological findings reveal wide variability in incidence and mortality, with older adults, low-resource settings, and exposure to high-risk medicines—such as antibiotics, antiretrovirals, and cardiovascular agents—representing key vulnerabilities. Despite advances in surveillance, underreporting, data quality issues, and methodological biases persist, particularly in low- and middle-income countries. Comparative analyses of pharmacovigilance platforms, including World Health Organization’s (WHO’s) VigiBase, EudraVigilance, and EU-ADR, highlight complementary strengths and the value of integrating spontaneous reporting with electronic health record analytics. Emerging statistical methods, including machine learning and federated analytics, offer improved signal detection timeliness and precision. Prevention strategies span prescriber-level, system-level, and patient engagement interventions. These include clinical decision support systems, pharmacogenomic-guided therapy, deprescribing protocols, mobile reporting applications, and wearable biosensors. Evidence shows that active surveillance and automated alerts outperform voluntary reporting, while digital tools can enhance detection and risk communication. However, implementation remains uneven due to infrastructure, workforce, and policy gaps. Looking forward, achieving the World Health Organization’s goal of halving severe medication-related harm by 2030 will require embedding ADR surveillance and prevention into universal health coverage frameworks. Policy priorities include mandating interoperable safety systems, harmonising international safety indicators, investing in capacity building for resource-limited settings, and aligning incentives with safer prescribing. Coordinated global action can bridge surveillance gaps, strengthen prevention, and build resilient, equitable pharmacovigilance systems, advancing both patient safety and sustainable health systems worldwide.