The International Maize and Wheat Improvement Center (CIMMYT) has identified the wheat (Triticum aestivum L.) irrigated area in the developing countries, which includes Egypt as Mega‐environment 1 (ME1). Agriculture intensification is expected to take place in this region to keep up with a continuously growing population, which might lead to more N application and losses because of the low N use efficiency (NUE) observed in this area. A panel of 40 wheat accessions including 10 commercially grown cultivars (CGCs), 10 elite lines from the CIMMYT, and 20 landraces from Egypt and Ethiopia were evaluated for grain yield (GY), grain protein content (GPC), NUE, agronomic NUE (AGNUE), stem rust, leaf rust, plant height (PH), leaf area, and total chlorophyll content (TCC), under four N levels. The panel was planted in two growing seasons (i.e., 2015–2016 and 2016–2017) and two locations. The results indicated that most of the CGCs were considered N efficient and N responsive. On the other hand, most landraces were N inefficient and nonresponsive because they produced higher GPC, PH, and TCC but had lower GY, AGNUE, and NUE. Furthermore, the landraces were less sensitive to the excessive N supply. ‘Sakha 94’, a commercially grown cultivar, was the most N efficient and N responsive; hence, it produced the highest GY at all N levels. The overall results might be scaled up to cover other Mediterranean basin regions that have similar environmental conditions.