Information is limited on the effects of climate variability on cowpea (Vigna unguiculata L.) and winter wheat (Triticum aestivum L.) yields in the semiarid region of the southern US. Using the Decision Support System for Agrotechnology Transfer (DSSAT) crop model and weather data spanning 81 years, we assessed the impact of El Niño-Southern Oscillation (ENSO) on the grain yields of these crops in the Llano Estacado region of the southern US as affected by cowpea and wheat planting dates and N application rate. Simulated results showed that the El Niño phase of ENSO produced about 30% more yields of mono-cropped cowpea than those produced under the La Niña phase, especially with the cowpeas planted in July. The cowpea yields under El Niño were about 10% more than the 81-year average normal yield, whereas those under La Niña were about 20% less. At the N rates of 0, 50, and 100 kg·ha −1 , regardless of wheat planting dates, the El Niño years produced, respectively, about 8%, 40%, and 60% higher wheat yields than those produced in the La Niña years, and about 5%, 20%, and 27% more than the 81-year average normal yield. In the La Niña years, the wheat yields at 0, 50, and 100 kg N ha −1 were, respectively, about 5%, 15%, and 20% less than the normal yield with similar N levels. The impact of ENSO on wheat yields under cowpea-wheat double-cropping systems was significant, especially for the wheat crops planted on October 15 (October 30) or later following the cowpea crops planted in June (July). At zero N, the mono-cropped wheat yields were not impacted by ENSO due to N limitation. However, the double-cropped wheat yields were impacted by ENSO even when no N fertilizer was applied due to high soil N status caused by N transfer from cowpea stover residues and roots. Results indicated that management strategies need to be attentive to ENSO forecasts and adjust potential planting dates and N application rates with the ENSO phase to avert risks of crop failure and economic loss.