Lysine-specific demethylase 1 (LSD1/KDM1A) is a nuclear flavin-dependent enzyme that regulates chromatin dynamics and gene transcription, and its dysregulation is closely associated with cancer progression and conventional chemotherapeutic resistance. In our present study, a series of purine-based small-molecule derivatives were rationally designed and synthesized for LSD1 inhibition. Structure–activity relationship considerations were applied to enhance biological efficacy in oral cancer cells. Hit molecule 14 was identified based on its potent cytotoxicity against CAL27 oral cancer cells (IC50 = 6.36 ± 0.2 μM) and the most desirable safety towards normal oral epithelial (NOE) cells (IC50 = 43.68 ± 2.57 μM). Compound 14 demonstrated moderate LSD1 inhibition (IC50 = 18.4 ± 3.11 μM) in a biochemical assay and excellent in vitro pharmacokinetic properties. This compound rewired the key cell death pathways in oral cancer cells via LSD1-modulated transcriptional reprogramming. Compound 14 exhibited pronounced lysosomal dysfunction, including lysosomal membrane destabilization and enhanced acidification in CAL27 cells. Compound 14 induced lysosomal damage in CAL27 cells and was identified as an early initiating event to activate the pyroptotic cell death pathway, marked by inflammasome-associated caspase-1 activation, cleavage of gasdermin D (GSDMD), and membrane pore formation. Concurrent activation of caspase-3/7 and apoptosis in CAL27 cells indicated a functional crosstalk between apoptotic and pyroptotic signaling downstream of epigenetic modulation, supported by transcriptome analysis. LD50 of compound 14 was determined to be greater than 2000 mg/kg in Sprague–Dawley rats following oral dosing and histopathological studies on major organs showed no identifiable morphological or structural abnormalities, strongly suggesting a favorable in vivo safety profile and low acute oral toxicity. These findings suggest that a rational epigenetic strategy to enforce transcriptional modulation of multiple and non-redundant cell death pathways can represent a promising approach to overcome chemoresistance in oral cancer.