The Nasia catchment is the reservoir with significant surface water resources in Northern Ghana and home to numerous subsistence farmers engaged in rainfed and dry season irrigation farming. Yet, there is little understanding of the hydro-climatic and land use/cover conditions of this basin. This study investigated trends, relationships and changes in hydro-climatic variables and land use/cover in addition to implications of the observable changes in the Nasia catchment over a period of 50 years. Parameters used for the study were minimum (Tmin) and maximum temperature (Tmax), wind speed (WS), sunshine duration (S), rainfall (R), relative humidity (RH), discharge (D) and potential evapotranspiration (PET) data, 15 years of remotely sensed normalized difference vegetation index (NDVI) data and 30 years of land use/cover image data. Results show that Tmin, Tmax, WS and PET have increased significantly (p < 0.05) over time. RH and S significantly declined. R, D and NDVI have not decreased significantly (p > 0.05). A significant abrupt change in almost all hydro-climatic variables started in the 1980s, a period that coincides with the occurrence of drought events in the region, except WS in 2001, R in 1968 and D in 1975, respectively. Also, D showed a positive significant correlation with RH, R and PET, but an insignificant positive relationship with S. D also showed a negative insignificant correlation with Tmin, Tmax and WS. Areas covered with shrubland and settlement/bare lands have increased to the disadvantage of cropland, forest, grassland and water bodies. It was concluded that climate change impact is quite noticeable in the basin, indicating water scarcity and possibilities of droughts. The analysis performed herein is a vital foundation for further studies to simulate and predict the effect of climate change on the water resources, agriculture and livelihoods in the Nasia catchment.