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Anaplastic lymphoma kinase (ALK) rearrangements are rare in lung squamous cell carcinoma (LSCC), with the clinical efficacy of ALK tyrosine kinase inhibitors (TKIs) in patients harboring uncommon ALK fusions remaining poorly characterized. We report here the first identification of a novel MTHFD1L-ALK fusion in a 63-year-old male with a heavy smoking history diagnosed with stage IIIC LSCC. The patient initially received induction therapy with the ALK TKI iruplinalkib, achieving a best response of stable disease (SD). Although subsequent chemoradiotherapy yielded a partial response (PR), disease progression occurred after four cycles of maintenance iruplinalkib, with a progression-free survival (PFS) of 8.28 months. Subsequent lorlatinib provided limited benefit, with disease progression at 5.3 months following treatment self-discontinuation. Retrospective immunohistochemical staining of ALK (D5F3) was negative despite the positive genomic finding. This case demonstrates limited clinical benefit from ALK inhibitors in LSCC with this novel fusion, expands the known mutational spectrum in non-small cell lung cancer (NSCLC), and underscores the critical importance of confirming novel fusions at the protein expression level through multimodal testing.