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Consumption of dietary lignans has been associated with reduced risk of chronic diseases, although the underlying mechanisms are unclear. We sought to determine if urinary excretion of ENL, the predominant microbial metabolite of dietary lignans, was associated with plasma protein abundance using a cross-sectional design based on data and plasma collected from 80 healthy participants in a randomized crossover, controlled feeding study. Proteomic analysis was performed on plasma samples collected at the end of each of two diet periods (160 samples total) using a customized antibody array corresponding to 2072 unique proteins. GC-MS was used to measure ENL excretion in 24-h urine samples collected in tandem with plasma. Linear mixed models tested the association between urinary enterolignan excretion and plasma protein abundance. Subsequently, over-representation analysis was conducted considering 17 a priori pathways with putative associations with enterolignan bioactivity in an exploratory approach. Controlling the false discovery rate at 10%, ENL excretion was inversely associated with seven proteins (FCRL5, PSCA, GAB1, LAPTM5, CCS, REG4, CEACAM1), and positively associated with two proteins (WAS and FBLN5). Over-representation analysis revealed associations of ENL excretion with estrogen and TNF signaling pathways, which were not significant after adjustment for false discovery. These ENL-associated proteins and pathways have potential implications in cancer prevention.