Recent advances in neuroscience have illustrated a multifaceted role of apolipoprotein E (apoE) in maintaining central nervous system homeostasis, particularly its vital roles in cellular metabolism and inflammation. ApoE orchestrates complex lipid trafficking networks within and between glial cells, regulating not only cholesterol distribution but also essential fatty acid metabolism and lipid droplet dynamics, which are critical for neuronal support and energy balance. Additionally, apoE influences glial and neuronal cells including astrocytes, microglia, oligodendrocytes, and neurons by modulating inflammatory signaling. At subcellular levels, apoE influences various organelles by regulating lysosomal functions in β-amyloid degradation, lipid accumulations, endoplasmic reticulum stress responses, unsaturated fatty acid accumulations in lipid droplets, peroxisomal activity, and nuclear functions. These organelle alterations that contribute to cellular dysfunctions are linked to Alzheimer’s disease (AD). Among its isoforms, apoE4 is strongly linked to an elevated risk and severity of AD. ApoE4 disrupts lipid metabolism, increases oxidative stress, and amplifies inflammatory responses, ultimately contributing to synaptic dysfunctions and neurodegeneration. Understanding the role of apoE in glial cell metabolism and its influence on neuronal health emphasizes critical therapeutic avenues for targeting metabolic and inflammatory pathways to mitigate neurodegenerative disorders, particularly AD. We explored therapeutic approaches such as modulation of apoE levels, structural modification of apoE, and indirect strategies that modulate lipid metabolism and inflammatory pathways, potentially halting or even reversing disease progression.