The effect of irrigation regimes and nitrogen (N) rates and their interactions on sesame (Sesamum indicum L.) yield is not completely evaluated; hence, the current study was conducted to investigate effects of these factors on sesame yield, N fertilizer use efficiency (NFUE), irrigation water use efficiency (IWUE), and seed oil content. The experiment was carried out in a semiarid region of Iran during 2016 and 2017 growing seasons outlined in a randomized complete-block design with a split factorial arrangement of treatments with three replicates. The main plots were allocated to the deficit and full irrigation regimes. Factorial combination of three N levels (0, 60, and 120 kg N ha(-1)) and three sesame cultivars (Oltan, Dashtestan, and Naz) were assigned to the subplots. When averaged over the years and cultivars, the results showed that the enhancement of applied N (0-120 kg N ha(-1)) increased sesame seed yield by 81% with full irrigation and by 51% with deficit irrigation. Maximum IWUE was found in Oltan treated with 120 kg N ha(-1) under full irrigation (0.26 kg m(-3)), while the minimum value was found in Naz treated with 0 kg N ha(-1) under deficit irrigation (0.05 kg m(-3)). The mean comparisons of NFUE showed that in the 60 kg N ha(-1) treatment, each kilogram of applied N led to the production of 13.8 and 4.5 kg seed ha(-1) with full and deficit irrigation, respectively. In contrast, in the 120 kg N ha(-1) treatment, each kilogram of applied N resulted in the production of 7.6 and 2.1 kg seed ha(-1) in the full and deficit irrigation regimes, respectively. In general, the optimal rates of N depended on the sesame cultivar and varied for different regimes of irrigation. Managing N fertilizer levels to meet sesame demands based on the amount of water applied and the type of cultivar not only prevented a negative environmental effect, but also increased yield and conserved agricultural inputs for sesame grown in arid and semiarid regions.