Objectives <p>This systematic review and meta-analysis are aimed at evaluating the incidence of adverse drug reactions (ADRs) following administration of clinically approved ultrasound contrast agents (UCAs) in adults and children, to assess risks in patients with cardiovascular disease and in pregnancy, and to evaluate the effectiveness of emergency management of severe ADRs.</p> Materials and methods <p>A PRISMA 2020 systematic review was conducted searching PubMed, Scopus, and Embase. Two reviewers independently screened, extracted data, and assessed quality. Incidence estimates were pooled when feasible, stratified by age group, contrast agent, and administration route.</p> Results <p>Seventy-four studies encompassing &gt; 1 million adults and &gt; 36,000 children were included, contributing multiple analytic cohorts to the quantitative synthesis. Severe acute ADRs were extremely rare (6 and 16 cases per 100,000 in adults and children, respectively) and absent following endocavitary administration in children. Non-severe acute ADRs occurred in 11 and 8 cases per 10,000 adults and children, respectively. Delayed reactions were very rare (&lt; 1 case per million in adults). No significant safety differences emerged between UCA products. The incidence of ADRs in patients with cardiovascular disease was analogous to the general population. No ADRs were reported in pregnant women. Standard emergency management was effective in almost all serious cases, though rare fatalities occurred.</p> Conclusion <p>UCAs show an excellent safety profile in adults and children, with very rare severe ADRs and few non-severe, typically self-limiting reactions. Strict adherence to recommended emergency management protocols mitigates the remaining risks, supporting safe use across a broad range of clinical indications.</p> PROSPERO registration <p>CRD42023432668.</p> Key Points <p><Emphasis Type="BoldItalic">Question</Emphasis> <i>What is the incidence, type, and severity of acute and delayed ADRs associated with clinically approved UCAs across different patient populations</i>?</p> <p><Emphasis Type="BoldItalic">Findings</Emphasis> <i>Severe acute adverse reactions are very rare, and non-severe reactions are rare and self-limiting, with no significant safety differences between adults, children, or patients with cardiovascular disease</i>.</p> <p><Emphasis Type="BoldItalic">Clinical relevant</Emphasis> <i>UCAs show an excellent safety profile across populations. These findings support their safe clinical use as reliable alternatives to iodine-based and gadolinium-based contrast agents in routine diagnostic imaging</i>.</p> Graphical Abstract <p></p>