Microplastics (MPs) are increasingly detected in human blood, particularly in individuals with cardiovascular diseases. However, understanding their direct interactions with blood cells remains challenging due to the lack of reliable detection methods. Available fluorescent probes suffer from spectral overlap with red blood cell (RBCs) autofluorescence, masking MP-induced effects. To overcome this, we proposed activatable near-infrared (NIR) probes that specifically target indicators in the RBCs. The NIR probes operate within a spectral range distinct from RBCs autofluorescence, exhibiting minimal background and a high turn-on response. Coupled with NIR imaging, this platform enabled the quantification of key redox indicators in zebrafish RBCs following exposure to pristine/aged biodegradable MPs poly(lactic acid) (PLA). Dose–response analyses revealed that PLA disrupted redox homeostasis in a dose-dependent manner. PLA showed greater toxicity than polystyrene, and aging further amplified their toxicity. Notably, the toxicity threshold of PLA and aged PLA was lower than the MP concentrations found in certain healthy human blood, and all MPs toxicity thresholds were below the levels detected in cardiovascular patients. This study provides a highly sensitive detection platform and underscores the urgent need to monitor the adverse effects of MPs on RBCs, particularly for PLA, for which monitoring data and toxicological evaluation remain critically lacking.