Background <p>Oxidative stress plays a pivotal role in the etiology of retinal degeneration, with hydrogen peroxide (H₂O₂) serving as a significant oxidant triggering oxidative stress within cellular environments. Meso-Zeaxanthin (MZ), a vital carotenoid, is renowned for its ocular health maintenance properties.</p> Methods <p>To assess MZ’s protective attributes against oxidative stress in human retinal pigment epithelial cells (ARPE-19), H₂O₂ was employed to induce oxidative stress in ARPE-19 cells. Subsequently, various parameters including cell viability, oxidative stress-related enzyme activities, reactive oxygen species (ROS) generation, cellular senescence, and cell cycle progression were evaluated. Additionally, in the realm of MZ bioavailability, microencapsulated MZ was investigated for its effects on human colorectal adenocarcinoma cells (Caco-2) and SD rat models. Subsequent evaluations encompassed cellular uptake, chiral structure assessment, and bioavailability determination.</p> Results <p>The findings underscore MZ’s remarkable antioxidant prowess, characterized by enhanced cell viability, diminished malondialdehyde (MDA) levels, augmented activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX), coupled with attenuated ROS production in H₂O₂-treated ARPE-19 cells. Remarkably, MZ downregulates ERK/JNK/P38MAPK expression in the MAPK pathway post-H₂O₂ exposure, thereby ameliorating oxidative stress-induced cellular damage. MZ microcapsule powder enhances Caco-2 uptake compared to the raw MZ group, after confirming negligible configurational selectivity differences in MZ uptake by Caco-2 cells. Furthermore, bioavailability experiments conducted in SD rats indicate elevated plasma zeaxanthin levels in the MZ microcapsule powder group compared to the raw MZ group.</p> Conclusions <p>Consequently, MZ has a strong antioxidant capacity and products formulated utilizing microencapsulation technology hold promise for enhancing in vivo bioavailability.</p>