Epigenetic analyses constitute an emerging approach for better understanding of the mechanisms underlying environmental responses and their role during acclimatization and adaptation across diverse ecosystems. The expansion of environmental epigenetic studies to a broader range of ecologically and environmentally relevant organisms will enhance the capability to forecast ecological and evolutionary processes, as well as to facilitate a retrospective assessment of stress exposures in biomonitor organisms through “epigenetic footprinting” analyses. With such purpose, the present study monitored spatial and temporal variation in abiotic parameters (temperature, salinity, pH, and horizontal visibility) over a 2-y period in a mangrove ecosystem located in North Biscayne Bay (North Miami, FL). The obtained data were subsequently compared with epigenetic modifications (global genome-wide DNA methylation levels) in the flat tree oyster Isognomon alatus, used as a sentinel model organism across experimental sites. The obtained results revealed a certain level of seasonality in temporal DNA methylation patterns, which seem to be primarily associated with changes in temperature and horizontal visibility. These results constitute the first long-term study combining spatial and temporal epigenetic analyses in a marine organism in its natural environment, laying the initial groundwork to assess the biomonitoring potential of environmental epigenetic analyses.