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Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which endothelial cell senescence (ECS) plays a key role. By integrating two GEO transcriptome datasets (145 IPF patients and 84 controls) and applying LASSO, SVM-RFE, and Boruta algorithms, four key ECS-related genes (ECSRGs), MYCT1, PLEKHA1, PCDH12, and PLXND1, were identified. MYCT1 and PLEKHA1 were downregulated by about 26% and 75%, while PCDH12 and PLXND1 were upregulated by 2.4- and 1.9-fold (p < 0.0001). The four-gene nomogram achieved 93.6% diagnostic accuracy. In TGF-β1-induced HUVECs, silencing MYCT1 or PLEKHA1 increased senescent cells by ~1.4-fold, whereas silencing PCDH12 or PLXND1 reduced α-SMA and COL1A1 levels by ~40%. In bleomycin-induced mice, valproic acid (VPA) lowered collagen deposition by ~60% and normalized gene expression. MYCT1 and PLEKHA1 act as anti-senescence factors, while PCDH12 and PLXND1 act as pro-fibrotic drivers. The four-gene model shows strong diagnostic potential, and VPA may serve as a therapeutic candidate targeting ECS in IPF.