Abstract: Neuroimmunology is emerging as a pivotal field, shedding light on the intricate dialogues between the central nervous system (CNS) and the immune system. This exploration is particularly significant in understanding microglia, the CNS’s innate immune cells, beyond the conventional conflation of “neuroinflammation” and “microglial activation.” This conflation has clouded the true complexity of these processes, potentially stalling scientific progress and the development of new therapies. We challenge the long-standing perspectives that have oversimplified these interactions, advocating for a deeper exploration of the dynamic relationship between neuroinflammation and microglial activation. By dissecting specific molecular pathways, we aim to illuminate their elaborate roles in neuroinflammatory responses, especially in the context of Alzheimer’s disease (AD). Here, neuroinflammation is not merely a passive observer or a direct antagonist but a complex agent in the disease’s progression. This article calls for a significant paradigm shift towards an integrative, multi-omics approach to neuroimmunology. Adopting such a comprehensive framework is crucial for advancing our understanding of neuroinflammatory conditions and paving the way for targeted therapeutic strategies for brain diseases.