Regulation of grain size is crucial for improving crop yield and is also a basic question in developmental biology. However, the genetic and molecular mechanisms underlying grain size control in crops remain largely unknown despite their central importance. Here we report that the MEI2-LIKE PROTEIN 4 (OML4) encoded by the LARGE1 gene is phosphorylated by the GLYCOGEN SYNTHASE KINASE 2 (GSK2) and negatively controls grain size and weight in rice. Loss of function of OML4 leads to large and heavy grains, while overexpression of OML4 causes small and light grains. OML4 regulates grain size by restricting cell expansion in the spikelet hull. OML4 is expressed in developing panicles and grains, and the GFP-OML4 fusion protein is localized in the nuclei. Biochemical analyses show that the GSK2 physically interacts with OML4 and phosphorylates it, therefore possibly influencing the stability of OML4. Genetic analyses support that GSK2 and OML4 act, at least in part, in a common pathway to control grain size in rice. These results reveal the genetic and molecular mechanism of a GSK2-OML4 regulatory module in grain size control, suggesting that this pathway is a suitable target for improving seed size and weight in crops.