The pathogenesis of neurodegenerative diseases (NDDs) is fundamentally linked to complex and profound alterations in metabolic networks within the brain, which critically exhibit significant spatial heterogeneity. Conventional bulk metabolomics, while powerful for identifying overall metabolic shifts, inherently lacks spatial resolution, a methodological limitation that prevents the interrogation of critical metabolic dysregulation within discrete anatomical brain regions and specific cellular microenvironments, thereby constraining a more profound understanding of the core pathological mechanisms that initiate and drive NDDs. Addressing this critical gap, spatial metabolomics, with mass spectrometry imaging (MSI) as its centerpiece, has emerged as a transformative approach that uniquely overcomes these limitations by enabling the high-resolution, simultaneous detection, and precise localization of hundreds to thousands of endogenous molecules—including primary metabolites, complex lipids, neurotransmitters, neuropeptides, and essential metal ions—directly in situ from tissue sections. This powerful capability provides an unprecedented and indispensable spatial perspective for investigating the intricate and heterogeneous chemical landscape of NDD pathology, opening new avenues for discovery. Accordingly, this review provides a comprehensive overview of the field, beginning with a discussion of the technical characteristics, optimal application scenarios, and current technological limitations of major MSI platforms, such as the widely adopted matrix-assisted laser desorption/ionization (MALDI)-MSI, the high-resolution technique of secondary ion mass spectrometry (SIMS)-MSI, and the ambient ionization method of desorption electrospray ionization (DESI)-MSI, alongside other innovative and emerging techniques. We then highlight its pivotal applications in NDD research, particularly in elucidating the profound chemical heterogeneity within distinct pathological microenvironments, including mapping the unique molecular signatures surrounding amyloid-beta (Aβ) plaques, defining the metabolic consequences of neurofibrillary tangles composed of hyperphosphorylated tau protein, and characterizing the lipid and metabolite composition of Lewy bodies. Moreover, we explore the crucial role of this technology in delineating detailed metabolic vulnerability maps across the brain, which help to reveal the underlying biochemical reasons why certain neuronal populations and anatomical regions are selectively susceptible to degeneration while others remain resilient. Looking beyond current applications, we also extensively consider the immense synergistic potential of integrating spatial metabolomics with other cutting-edge research methodologies. This includes its strategic combination with three-dimensional brain organoid models to recapitulate and study disease-relevant metabolic processes, its linkage with multi-organ axis studies to explore how systemic metabolic health influences neurodegeneration, and its powerful convergence with single-cell and subcellular analyses to achieve unparalleled molecular resolution. In conclusion, this review not only summarizes the current state and pivotal role of spatial metabolomics but also provides a forward-looking perspective on its transformative potential, projecting its continuing impact on advancing fundamental NDD research and its trajectory toward tangible clinical applications, spanning from the discovery of novel biomarkers for early diagnosis to the development of innovative platforms for high-throughput drug screening and the ultimate realization of precision medicine for individuals affected by these devastating disorders.