Wheat is an important crop in the highlands of Northern Ethiopia and climate change is expected to be a major threat to wheat productivity. However, the potential impacts of climate change and adaptation on wheat yield has not been documented for this region. Wheat field experiments were carried out during the 2011–2013 cropping seasons in Northern Ethiopia to: (1) calibrate and evaluate Agricultural Production Systems sIMulator (APSIM)-wheat model for exploring the impacts of climate change and adaptation on wheat yield; (2) explore the response of wheat cultivar/s to possible change in climate and carbon dioxide (CO2) under optimal and sub-optimal fertilizer application and (3) assess the impact of climate change and adaptation practices on wheat yield based on integration of surveyed field data with climate simulations using multi-global climate models (GCMs; for short- and mid-term periods) for the Hintalo-Wajrat areas of Northern Ethiopia. The treatments were two levels of fertilizer (optimal and zero fertilization); treatments were replicated three times and arranged in a randomized complete block design. All required information for model calibration and evaluation were gathered from experimental studies. In addition, a household survey was conducted in 2012 in Northern Ethiopia. Following model calibration and performance testing, response of wheat to various nitrogen (N) fertilizer rates, planting date, temperature and combinations of other climate variables and CO2 were assessed. Crop simulations were conducted with future climate scenarios using 20 different GCMs and compared with a baseline. In addition, simulations were carried out using climate data from five different GCM with and without climate change adaptation practices. The simulated yield showed clear responses to changes in temperature, N fertilizer and CO2. Regardless of choice of cultivar, increasing temperatures alone (by up to 5 °C compared with the baseline) resulted in reduced yield while the addition of other factors (optimal fertilizer with elevated CO2) resulted in increased yield. Considering optimal fertilizer (64 kg/ha N) as an adaptation practice, wheat yield in the short-term (2010–2039) and mid-term (2040–2069) may increase at least by 40%, compared with sub-optimal N levels. Assuming CO2 and present wheat management is unchanged, simulation results based on 20 GCMs showed that median wheat yields will reduce by 10% in the short term and by 11% in the mid-term relative to the baseline data, whereas under changed CO2 with present management, wheat yield will increase slightly, by up to 8% in the short term and by up to 11% in the mid-term period, respectively. Wheat yield will substantially increase, by more than 100%, when simulated based on combined use of optimal planting date and fertilizer applications. Increased temperature in future scenarios will cause yield to decline, whereas CO2 is expected to have positive impacts on wheat yield.