Background: Human metapneumovirus (hMPV) has been increasingly recognized as a major contributor of respiratory infections in all age groups. Owing to its recent discovery, available data on the burden of hMPV in adults are still scant and heterogeneous. Here, we aimed to explore epidemiology, symptomatic profile, and mortality related to hMPV among Italian adults. Methods: We performed an integrated analysis of several community-based and hospital-based studies conducted in Genoa (Italy) between 2014 and 2025. Adults aged ≥ 18 years prescribed with ≥ 1 molecular test for hMPV were eligible. Results: Of 21,580 and 2,671 adults included in the hospital-based and community-based studies, 376 and 117, respectively, tested positive for hMPV. Seasonal (November to April) hMPV detection rate was higher in the community-based (4.4%; 95% CI: 3.6–5.2%) than in the hospital-based (2.4%; 95% CI: 2.1–2.6%) studies. Most detections occurred during the spring months. Each 10-year increase in age was associated with an 11% increase in the odds of hMPV positivity [adjusted odds ratio (aOR) 1.11; 95% CI: 1.05–1.18]. Clinical presentation of hMPV resembled that of the phylogenetically related respiratory syncytial virus. Among hMPV-positive inpatients, 7.3% (95% CI: 4.3–11.5%) died during their hospital encounter. In-hospital mortality was associated with residency in long-term care facilities (aOR 8.73; 95% CI: 2.63–29.15) and cancer (aOR 4.51; 95% CI: 1.50–14.35). Conclusions: hMPV is a common virological finding in outpatient and inpatient adults and is responsible for a measurable burden, especially among the most frail older adults.