Factor XIa (FXIa) has emerged as a promising target for novel anticoagulant development since inhibiting it can reduce thrombosis without significant bleeding risks. Despite a few FXIa inhibitors entering clinical trials, none have been approved for the market yet. Here, we present highly selective and orally bioavailable FXIa inhibitors derived from compound 1, 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one. Structure-activity relationship studies led to the discovery of promising 1-(pyridin-2-ylmethyl)pyridin-2(1H)-one-based FXIa inhibitors 37, 39b, 43, and 46b, which exhibited enhanced FXIa potency and selectivity compared to asundexian, an FXIa inhibitor in phase III clinical trials. Their anticoagulant activity was also comparable to or greater than that of asundexian. Compound 43 significantly reduced thrombosis in both FeCl₃-induced mouse and rabbit arterial thrombosis models, demonstrating superior efficacy compared to asundexian. Importantly, 43 did not increase bleeding risks and exhibited a favorable safety profile in mice, suggesting its potential as a promising FXIa inhibitor for the treatment of thrombosis.