Frontotemporal dementia (FTD) is a neurodegenerative disorder marked by progressive neuronal loss in the frontal and temporal lobes, driven by distinct molecular and cellular pathologies. This chapter explores the critical intersection of neuroinflammation and autophagy–lysosomal dysfunction as central mechanisms in FTD pathogenesis. Key genetic contributors MAPT, GRN, and C9ORF72 initiate diverse pathological cascades, including tau aggregation, TDP-43 mislocalization, and impaired vesicular trafficking to disrupt proteostasis and immune regulation. Autophagy failure leads to the accumulation of toxic proteins and organelles, which activate microglia and amplify pro-inflammatory signaling through pathways such as nuclear factor kappa B (NF-κB), NLRP3 inflammasome, and cGAS-STING. This self-reinforcing cycle exacerbates neuronal vulnerability and accelerates disease progression. Additionally, stress granule persistence, mitochondrial dysfunction, and lysosomal stress further entrench this pathological feedback loop. Genetic modifiers like transmembrane protein 106B (TMEM106B) intensify these effects, influencing disease severity and onset. Understanding the mechanistic convergence of inflammation and proteostatic failure is essential for developing effective interventions aimed at halting or reversing neurodegeneration in FTD.