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For decades, multiple anthropogenic stressors have threatened the Galápagos Islands. Widespread marine pollution such as oil spills, persistent organic pollutants, metals, and ocean plastic pollution has been linked to concerning changes in the ecophysiology and health of Galápagos species. Simultaneously, illegal, unreported, and unregulated fishing are reshaping the composition and structure of endemic and native Galápagos pelagic communities. In this novel review, we discuss the impact of anthropogenic pollutants and their associated ecotoxicological implications for Galápagos species in the face of climate change stressors. We emphasize the importance of considering fishing pressure and marine pollution, in combination with climate‐change impacts, when assessing the evolutionary fitness of species inhabiting the Galápagos. For example, the survival of endemic marine iguanas has been negatively affected by organic hydrocarbons introduced via oil spills, and endangered Galápagos sea lions exhibit detectable concentrations of DDT, triggering potential feminization effects and compromising the species' survival. During periods of ocean warming (El Niño events) when endemic species undergo nutritional stress, climate change may increase the vulnerability of these species to the impacts of pollutants, resulting in the species reaching its population tipping point. Marine plastics are emerging as a deleterious and widespread threat to endemic species. The Galápagos is treasured for its historical significance and its unparalleled living laboratory and display of evolutionary processes; however, this unique and iconic paradise will remain in jeopardy until multidisciplinary and comprehensive preventative management plans are put in place to mitigate and eliminate the effects of anthropogenic stressors facing the islands today. We present a critical analysis and synthesis of anthropogenic stressors with some progress from local and international institutional efforts and call to action more precautionary measures along with new management philosophies focused on understanding the processes of change through research to champion the conservation of the Galápagos. Integr Environ Assess Manag 2023;19:870–895. © 2022 SETAC Key Points: Ocean pollution, anthropogenic climate change, and fishing pressure (illegal, unregulated, and unreported fishing) are driving factors reshaping evolutionary processes and affecting marine biodiversity in the complex social–ecological systems of the UNESCO Global Heritage Site, Galápagos Islands.The combination of chemical pollution, marine debris, ocean plastics, climate change, and overfishing are conspiring to further contaminate marine life and food webs, which has obvious implications for ecosystems and the ocean, but also for the health of the islands' coastal communities.A proactive policy framework is essential to addressing and combating the multiple anthropogenic stressors, resulting from the intertwined nature of chemical pollution, climate change, and fishery pressure, across the biological and socioeconomic levels of organization in the Galápagos Islands.Although efforts for conservation and management are classic arenas to continue preserving the Galápagos Islands, an opportunity to frame solution‐oriented research to better understand the processes of change and conservation management remaking nature in the Anthropocene era is critical. [ABSTRACT FROM AUTHOR]