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Subclassification of NSCLC is critical for therapeutic decision-making, particularly in small biopsies and cytology specimens where ancillary testing must be limited. Although the TTF-1/p40 panel is widely used to distinguish adenocarcinoma (ADC) from squamous cell carcinoma, a subset of NSCLCs remains unclassified, highlighting the need for adjunctive markers. Periodic acid-Schiff with diastase (PAS-D) is readily available but underutilized. We retrospectively reviewed 2611 NSCLC specimens from 2298 patients. Diagnosis was based on morphology alone in 38.6% of cases, while ancillary testing was required in 57.7%. Among 287 TTF-1_neg/p40_neg tumors, 30.3% were classified as ADC using PAS-D and/or Napsin A. PAS-D demonstrated higher sensitivity than Napsin A (71.8% vs. 69.3%), and markedly outperformed Napsin A in TTF-1-negative ADCs (89.7% vs. 25.9%, p < 0.001). This finding reflects biological differences between terminal respiratory unit-derived ADCs and non-terminal airway tumors, in which PAS-D positivity is more diagnostically informative. Combined testing improved sensitivity, with the TTF-1/PAS-D panel achieving 97.5%. This study highlights the underappreciated diagnostic value of PAS-D, particularly in TTF-1-negative tumors. PAS-D represents a simple, effective adjunct to routine diagnostic panels. Therefore, incorporating PAS-D into routine panels can enhance NSCLC subclassification, particularly in TTF-1_neg/p40_neg tumors and support accurate diagnosis and optimal clinical management.