Oncogenic signaling pathways-guided alternative splicing events and their clinical prognostic values were investigated in lung squamous cell carcinoma (LUSC). RNAseq and AS data of LUSC were obtained from TCGA and SpliceSeq database, respectively. Pathway enrichment-guided activity study of alternative splicing (PEGASAS) analysis was performed to evaluate the activity of oncogenic pathways. We identified 4229 AS events in 2311 genes significantly associated with the Hallmark_Myc_Targets_V1 pathway. Twenty-nine prognostic Myc guided-AS events classified LUSC into 3 subtypes, of which Cluster 1 subtype showed the worst prognosis, while cluster 2 subtype showed a favorable prognosis. A prognostic model based on 10 most contributive prognostic AS events identified by LASSO could effectively stratify LUSC patients into high- and low-risk groups. The high-risk group was associated with worse survival and contained more samples in poor prognostic subtype (cluster 1). GSEA revealed that cell adhesion and immune response pathways were significantly enriched in the high-risk group, and AS pathways in the low-risk group. Fifty-nine regulatory SFs were identified to regulate these 10 AS events. Myc-guided AS events could classify LUSC samples into subtypes with significantly different survival. A prognostic model based on 10 Myc-guided AS events could predict the survival of LUSC.