Climate change and desertification are global issues that are affecting agricultural activities in Sub-Saharan Africa. These phenomena have made it challenging for smallholder farmers to cope with the emerging global food crises. This article examines the evidence of desertification and climate change and how smallholder farmers in the Upper East Region of Ghana are responding to these threats. Primary data was analysed through interviews and focus group discussions. We used Landsat satellite-based annual mean Normalized Difference Vegetation Index, climate, crop production data, and reports from the Ministry of Food and Agriculture and other NGOs as secondary sources. We interviewed eighty respondents using case history and snowball sampling. The mean annual NDVI declined from 0.5 in 1998 to −0.10 in 2022. NDVI values suggest a decline in green vegetation health to a negative value, suggesting a non-vegetative surface. This means that the process of desertification has progressed to severe levels, resulting in little to no vegetation cover on the land surface. Similarly, rainfall data suggests a sharp decline in annual rainfall while farmers change the types of crops and the timing of planting. Farmers discussed the impact of climate change and desertification on their livelihoods. They have implemented approaches like using synthetic fertilisers, planting drought-resistant crops, practising dry-season farming, irrigating their crops, and building social support networks. Food insecurity and land degradation are major issues due to continuous cropping and population growth. Smallholder farmers suggest providing them with affordable, drought-resistant seedlings with shorter gestation periods to increase food production and avoid insecurity.