Effective and comprehensive regional-scale marine conservation requires fine-grained data on the spatial patterns of threats and their overlap. To address this need for the Papahānaumokuākea Marine National Monument (Monument) in Hawaii, USA, spatial data on 14 recent anthropogenic threats specific to this region were gathered or created, including alien species, bottom fishing, lobster trap fishing, ship-based pollution, ship strike risks, marine debris, research diving, research equipment installation, research wildlife sacrifice, and several anthropogenic climate change threats i.e., increase in ultraviolet (UV) radiation, seawater acidification, the number of warm ocean temperature anomalies relevant to disease outbreaks and coral bleaching, and sea level rise. These data were combined with habitat maps and expert judgment on the vulnerability of different habitat types in the Monument to estimate spatial patterns of current cumulative impact at 1 ha (0.01 km2) resolution. Cumulative impact was greatest for shallow reef areas and peaked at Maro Reef, where 13 of the 14 threats overlapped in places. Ocean temperature variation associated with disease outbreaks was found to have the highest predicted impact overall, followed closely by other climate-related threats, none of which have easily tractable management solutions at the regional scale. High impact threats most tractable to regional management relate to ship traffic. Sensitivity analyses show that the results are robust to both data availability and quality. Managers can use these maps to (1) inform management and surveillance priorities based on the ranking of threats and their distributions, (2) guide permitting decisions based on cumulative impacts, and (3) choose areas to monitor for climate change effects. Furthermore, this regional analysis can serve as a case study for managers elsewhere interested in assessing and mapping region-specific cumulative human impacts.