A2E, a major pyridinium bisretinoid component of retinal lipofuscin, functions as a photosensitizer that undergoes blue light-induced oxidation, contributing to oxidative stress in age-related macular degeneration (AMD). This study investigated whether lipophilic antioxidants and non-antioxidant hydrophobic molecules protect A2E primarily through reactive oxygen species (ROS) quenching, modulation of its local microenvironment, or both. A2E was irradiated with blue light in the presence or absence of hydrophobic additives: palmitic acid (PA), vitamin E, β-carotene, lutein, zeaxanthin, and zeaxanthin dipalmitate (ZDP). Fluorescence spectroscopy assessed photophysical changes. A2E degradation was quantified using reverse-phase LC-MS with optimized electrospray ionization, distinguishing actual A2E loss from fluorescence artifacts. All additives significantly reduced A2E degradation, with protection strongly correlated with hydrophobicity. ZDP preserved about 76% of A2E, and even non-antioxidant PA offered marked protection. Fluorescence spectra showed compound-specific emissions and, notably, increased A2E fluorescence intensity with a blue shift, particularly with ZDP and PA, suggesting enhanced co-localization in lipid-rich domains. These results reveal two complementary protective mechanisms: classical ROS scavenging by carotenoids and vitamin E, and microenvironment remodeling by highly lipophilic molecules like ZDP and PA. The microenvironmental remodeling effects of lipophilic compounds remain speculative and warrants further investigation. Thus, strategies targeting both ROS neutralization and A2E’s hydrophobic niche may effectively mitigate blue-light-driven retinal damage in AMD.