Rice, wheat, maize, millet, and barley are the five major staple cereal crops in Nepal. However, their yields are low, and imports are needed to meet domestic demand. In this study, we quantify the gap between current and potentially attainable yields in Nepal, estimate how much additional fertilizer and irrigation are required to close the gap, and assess if self-sufficiency can thus be achieved. For this, we first test the ability of the crop model EPIC to reproduce reported yields in 1999–2014 accurately. On average, simulated and reported yields at the national level were in the same range, but at the district level, the error was large, as the resolutions of the available climate and soil input data were not high enough to depict the heterogenic conditions in Nepal adequately. In the main study, we show that average yield gaps in Nepal amount to 3.0 t/ha (wheat), 2.7 t/ha (rice), 2.9 t/ha (maize), 0.4 t/ha (barley), and 0.5 t/ha (millet). With additional irrigation and fertilization, yields can be increased by 0.1/2.3 t/ha (wheat), 0.4/1.3 t/ha (rice), 1.6/1.9 t/ha (maize), 0.1/0.3 t/ha (barley), and 0.1/0.4 t/ha (millet), respectively. The results show that providing reliable and affordable access to fertilizer should be a priority for closing yield gaps in Nepal.