Microplastic pollution poses an escalating concern, particularly in coastal lagoons rich in biodiversity. This study delved into the occurrence of microplastics (MPs) in Magallana gigas (formerly Crassostrea gigas) from the Orbetello and Varano coastal lagoons (Italy), also investigating the response of these filter-feeding organisms to various colors (P = pink; B = blue; W = white) of high-density polyethylene (HDPE) MP fragments. Oysters were exposed for 7 days under controlled conditions. Subsequently, the oysters underwent analysis for both MP presence and biochemical markers of oxidative stress. Diverse ingestion rates of HDPE were noted among oysters from the two lagoons, eliciting antioxidant responses and modifying baseline activity. The two-way ANOVA revealed the significant effects of treatment (control; HDPE_B; HDPE_P; HDPE_W), site, and the interaction between treatment and site on all biomarkers. Non-metric multidimensional scaling showed a divergent effect of HDPE color on biomarkers. Further investigation is warranted to elucidate the mechanisms underlying the influence of MP color, dose-dependent effects, and the long-term impacts of exposure. Comprehending these intricacies is imperative for devising effective strategies to mitigate plastic pollution and safeguard marine health.