Metabolic disorders such as diabetes and hypergalactosemia often induce oxidative damage and mitochondrial dysfunction in the lens, leading to metabolic cataracts. Although surgical intervention remains the primary treatment, its associated risks and complications underscore the need for pharmacological alternatives with multifaceted protective effects. Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6), a novel enzyme mimic of microperoxidase-11, has demonstrated potent reactive oxygen species (ROS)-scavenging activity in vivo. Our previous studies have confirmed its efficacy in mitigating lens opacity and enhancing antioxidant enzyme levels in galactose-induced cataract models. To further elucidate the underlying mechanisms, we established both in vivo galactose-induced rat models and in vitro lens epithelial cell models. The results revealed that DhHP-6 significantly alleviated lens opacity by activating the NRF2/KEAP1/HO-1 pathway, thereby boosting antioxidant enzyme activity, restoring ATP levels, and inhibiting apoptotic signaling. Crucially, in vitro analyses confirmed DhHP-6's ability to maintain mitochondrial structural integrity and functional homeostasis through this pathway, thereby preventing the initiation of apoptosis cascades. These findings demonstrate that DhHP-6 attenuates metabolic cataract progression through multi-target mechanisms orchestrated by the NRF2/KEAP1/HO-1 pathway, integrating antioxidative defense, mitochondrial homeostasis restoration, and apoptosis inhibition into a unified therapeutic strategy.