Field experiments were carried out in 2018 and 2019 cropping seasons to determine the effect of fertilizer application on soil properties and yield of sesame varieties in Southern Guinea and Sudan Savanna Agro-ecological Zones of Nigeria. Treatments consisted of three varieties of sesame (Jigida, NCRIBEN-01M and NCRIBEN-032) and four levels of NPK 15:15:15 fertilizer (0, 50,100 and 150 kg ha-1). Treatments were laid out in a randomized complete block design (RCBD) and replicated thrice. Prior to planting, surface (0-15 cm) soil samples were collected from eight points and bulked; post-harvest composite soil samples were also collected on the basis of treatments. All soil samples were analyzed using standard analytical procedures. Data on yield parameters collected include number of capsules per plant, number of seeds per capsule, length of capsule (cm), 1000 capsule weight (g), 1000 seeds weight (g) and seed yield (t ha-1). The crop data generated from the study were subjected to Analysis of Variance (ANOVA) using Genstat Release 10.3 DE after which significant means were separated using Least Significant Difference (LSD) at 5 % level of probability. Results indicated that the soils of both locations were inherently poor in essential plant nutrients. The improved varieties (NCRIBEN-01M and NCRIBEN-032) performed better than the local variety in terms of yields in both cropping seasons. Sesame yield increased with increase in fertilizer application rates up to 150 kg ha-1. The effect of varieties on soil properties did not differ significantly however, the improved varieties left lower essential nutrients in soil when compared with the local variety. Fertilizer application at 150 kg ha-1 favoured the retention of organic matter as well as other essential nutrient elements in soil. Location effect showed that the Potiskum soil had more nutrients than that of Makurdi. For sustainable sesame production and maintenance of soil fertility in both locations, application of 150 kg ha-1 of NPK 15:15:15 to sesame fields is recommended.