Background <p>Measles is a highly contagious, vaccine-preventable viral disease that remains a major public health concern in low-income countries like Ethiopia, particularly in the Amhara Region. Despite ongoing vaccination efforts, periodic outbreaks continue to occur. In this regard, data on the recent epidemiological patterns, temporal trends, and spatial distribution of measles cases in the region are limited. Therefore, this study was conducted to assess the incidence, temporal trends, and spatial clustering of measles cases in Amhara region from 2019 - 2024 to inform targeted interventions and outbreak responses.</p> Methods <p>A retrospective analysis of regional measles surveillance data from 2019-2024 was conducted in Amhara region, Ethiopia. Enzyme linked immunosorbent assay method employed for measles confirmation using anti-measles specific immunoglobulin M using EUROIMMUN test kit. Descriptive statistics and trend analysis was conducted using SPSS version 26. Spatial analysis to determine the spatial distribution, case distribution pattern (autocorrelation), and hot spot analysis was performed through ArcGIS tool. SaTScan statistics tool was used to identify the significant primary and secondary measles case clusters in the Amhara region.</p> Results <p>Out of a total of 18,468 reported measles suspected cases, 11354 (61%) were classified as clinically compatible, 3657 (20%) were epidemiologically linked, 1886 (10%) were discarded cases, and 1571 (9%) were laboratory-confirmed. The highest proportion of cases (36.5%) occurred among children aged 5–14 years, followed by adults aged ≥15 years (26%). Males accounted for the majority of cases (54%). Among all cases, 4.7% were ineligible for vaccination due to being under 9 months of age. Geographically, the highest number of cases were reported from Waghimra zone (16.6%), followed by Central Gondar (12.4%), Oromo Special zone (9.6%), and East Gojjam (9%). The crude incidence rate per 100,000 population increased from 0.53 to 2.13, peaking in 2023. Measles cases showed clear seasonal trends, with peaks occurring during the spring (March-May) and autumn (September-November) seasons. Spatial autocorrelation analysis indicated clustering of measles cases. Hotspots were identified at the woreda level in Waghimra, Oromo Special zone, South Gondar, and North Shoa zones. Significant primary clusters were also detected in the same zones.</p> Conclusion <p>Measles transmission persists in Amhara Regional State, with increasing incidence and distinct spatial and temporal patterns. Immunity gaps in older children and geographically clustered outbreaks highlight the need for enhanced vaccination strategies. Strengthening measles surveillance, prioritizing catch-up vaccination for older children, and implementing targeted immunization campaigns in hotspot areas during peak transmission seasons are recommended.</p> Clinical trial <p>Not applicable.</p>