Grain size is one of the key agronomic traits that determine grain yield in crops. However, the mechanisms underlying grain size control in crops remain elusive. Here we demonstrate that the OsMKKK10-OsMKK4-OsMAPK6 signaling pathway positively regulates grain size and weight in rice. Loss of OsMKKK10 function results in small and light grains, short panicles and semi-dwarf plants, while overexpression of constitutively active OsMKKK10 (CA-OsMKKK10) causes large and heavy grains, long panicles and tall plants in rice. OsMKKK10 interacts with and phosphorylates OsMKK4. We identify a gain-of-function mutant of OsMKK4 (large11-1D), which causes large and heavy grains. OsMKK4^A227T encoded by the large11-1D allele has stronger kinase activity than OsMKK4. Overexpression of a constitutively active OsMKK4 (OsMKK4-DD) also forms large grains. Further biochemical and genetic analyses reveal that OsMKKK10, OsMKK4 and OsMAPK6 function in a common pathway to control grain size. Thus, our findings reveal an important genetic and molecular framework for the OsMKKK10-OsMKK4-OsMAPK6 cascade-mediated control of grain size and weight in rice.