This investigation was aimed at contributing to develop a suitablemulti-biomarker approach for pollution monitoring in mangrove-lined Caribbean coastal systems using as sentinel species, the mangrove cupped oyster, Crassostrea rhizophorae. A pilot field study was carried out in 8 localities (3 in Nicaragua; 5 in Colombia), characterized by different environmental conditions and subjected to different levels and types of pollution. Samples were collected in the rainy and dry seasons of 2012–2013. The biological effects at different levels of biological complexity (Stress-on-Stress response, reproduction, condition index, tissue-level biomarkers and histopathology) were determined as indicators of health disturbance, integrated as IBR/n index, and compared with tissue burdens of contaminants in order to achieve an integrative biomonitoring approach. Though modulated by natural variables and confounding factors, different indicators of oyster health, alone and in combination, were related to the presence of different profiles and levels of contaminants present at low-to-moderate levels. Differentmixtures of persistent (As, Cd, PAHs) and emerging chemical pollutants (musk fragrances), in combination with different levels of organic and particulate matter resulting fromseasonal oceanographic variability and sewage discharges, and environmental factors (salinity, temperature) elicited a different degree of disturbance in ecosystemhealth condition, as reflected in sentinel C. rhizophorae. As a result, IBR/nwas correlatedwith pollution