Organ growth is determined by a coordinated combination of cell proliferation and cell growth and differentiation. Endoreduplication is often coupled with cell growth and differentiation, but the genetic and molecular mechanisms that link endoreduplication with cell and organ growth are largely unknown. Here we describe UBIQUITIN-SPECIFIC PROTEASE14 (UBP14), encoded by the DA3 gene, which functions as a negative regulator of endoreduplication. The Arabidopsis thaliana (Arabidopsis) da3-1 mutant shows large cotyledons, leaves and flowers with higher ploidy levels. UBP14 acts along with ULTRAVIOLET-B-INSENSITIVE4 (UVI4), an inhibitor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase, to repress endoreduplication. Also, UBP14 functions antagonistically with CELL CYCLE SWITCH52 A1 (CCS52A1), an activator of APC/C, to regulate endoreduplication. UBP14 physically associates with UVI4 both in vitro and in vivo, but does not directly interact with CCS52A1. Further results reveal that UBP14 influences the stability of cyclin A2;3 (CYCA2;3) and cyclin-dependent kinase B1;1 (CDKB1;1), two downstream components of the APC/C. Thus, our findings show how endoreduplication is linked with cell and organ growth by revealing important genetic and molecular functions for the ubiquitin-specific protease UBP14 and for the key cell-cycle regulators UVI4, CCS52A1, CYCA2;3 and CDKB1;1.