Panicle architecture is one of the most important agronomical traits that directly contribute to grain yield in rice (Oryza sativa L.). We report herein an in-depth characterization of two allelic larger panicle (lp) mutants that show significantly increased panicle size as well as improved plant architecture. Morphological analyses reveal that panicles of two mutants produced more inflorescence branches, especially the primary branches, and contained more grains. Moreover, mutant plants also display more lodging resistance than the wild type. The grain yield per plant in mutants is also increased, suggesting that mutant plants have useful potential for high grain yield in rice breeding. Map-based cloning reveals that LARGER PANICLE (LP) encodes a Kelch repeat-containing F-box protein. RNA in situ hybridization studies display that LP expression was enriched in the branch primordial region. Subcellular localization analyses demonstrate that LP is an endoplasmic reticulum (ER) localized protein, suggesting that LP might be involved in ER-associated protein degradation (ERAD). Using yeast two-hybrid assay and bimolecular fluorescence complementation analysis, we confirm that LP is an F-box protein and could interact with rice SKP1-like protein in an F-box domain-dependent manner. Quantitative real-time PCR results show that OsCKX2, which encodes cytokinin oxidase/dehydrogenase, is down-regulated evidently in mutants, implying that LP might be involved in modulating cytokinin level in plant tissues. These results suggest that LP plays an important role in regulating plant architecture, particularly in regulating panicle architecture, thereby representing promising targets for genetic improvement of grain production plants.