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During rice domestication and improvement, increasing grain yield to meet human needs was the primary objective. Rice grain yield is a quantitative trait determined by multiple genes, but the molecular basis for increased grain yield is still unclear. Here, we show that NUMBER OF GRAINS 1 (NOG1), which encodes an enoyl-CoA hydratase/isomerase, increases the grain yield of rice by enhancing grain number per panicle without a negative effect on the number of panicles per plant or grain weight. NOG1 can significantly increase the grain yield of commercial high-yield varieties: introduction of NOG1 increases the grain yield by 25.8% in the NOG1-deficient rice cultivar Zhonghua 17, and overexpression of NOG1 can further increase the grain yield by 19.5% in the NOG1-containing variety Teqing. Interestingly, NOG1 plays a prominent role in increasing grain number, but does not change heading date or seed-setting rate. Our findings suggest that NOG1 could be used to increase rice production.