Endemic island species face unprecedented threats, with many populations in decline or at risk of extinction. One important threat is the introduction of novel and potentially devastating diseases, made more pressing due to accelerating global connectivity, urban development, and climatic changes. In the Galápagos archipelago two important wildlife diseases: avian pox (Avipoxvirus spp.) and avian malaria (Plasmodium spp. and related Haemosporidia) challenge endemic species. San Cristóbal island has seen a paucity of disease surveillance in avian populations, despite the island's connectedness to the continent and the wider archipelago. To survey prevalence and better understand the dynamics of these two diseases on San Cristóbal, we captured 1205 birds of 11 species on the island between 2016 and 2020. Study sites included urban and rural lowland localities as well as rural highland sites in 2019. Of 995 blood samples screened for avian haemosporidia, none tested positive for infection. In contrast, evidence of past and active pox infection was observed in 97 birds and identified as strains Gal1 and Gal2. Active pox prevalence differed significantly with contemporary climatic conditions, being highest during El Niño events (~11% in 2016 and in 2019 versus <1% in the La Niña year of 2018). Pox prevalence was also higher at urban sites than rural (11% to 4%, in 2019) and prevalence varied between host species, ranging from 12% in medium ground finches (Geospiza fortis) to 4% in Yellow Warblers (Setophaga petechial aureola). In the most common infected species (Small Ground Finch: Geospiza fuliginosa), birds recovered from pox had significantly longer wings, which may suggest a selective cost to infection. These results illustrate the threat future climate changes and urbanization may present in influencing disease dynamics in the Galápagos, while also highlighting unknowns regarding species-specific susceptibilities to avian pox and the transmission dynamics facilitating outbreaks within these iconic species.