Hot pepper is one of the most important spice vegetable crops in Ethiopia and is widely cultivated for dry pod production. However, its productivity is low in Ethiopia due to degraded soil fertility and an unbalanced nutrient supply in the soil. An experiment was conducted to evaluate the effect of NPS fertilizer and cattle manure (CM) on soil chemical properties and hot pepper dry pod yield under irrigation in Jabi Tehnan. This experiment was arranged in factorial combinations of four NPS fertilizer (0, 100, 200, and 300 kg ha−1) and four CM (0, 5, 10, and 15 t ha−1) levels in a randomized complete block design with three replicates. Soil chemical properties, hot pepper phenology, growth, yield, and yield-related traits were recorded and analyzed using SAS software version 9.4. The main and interaction effects of NPS and CM fertilizers had a significant effect on soil chemical properties, hot pepper phenology, growth, yield, and yield-related traits. The combination of NPS fertilizer and CM significantly increased soil chemical properties and hot pepper traits. However, soil chemical properties and hot pepper yield traits showed a somewhat decreasing trend as the combination levels of two fertilizers further increased. The highest marketable (2.90 t ha−1) and total dry pod yield (2.99 t ha−1) were produced at the combination of 200 kg NPS ha−1 and 15 t CM ha−1. However, the partial budget analysis showed that the combination of 200 kg NPS ha−1 and 10 t CM ha−1 had the highest net benefit with an acceptable MRR and can be recommended for profitable hot pepper dry pod production in the study area. However, the experiment was limited to a single location and variety; it should be repeated at multiple locations over the seasons to make a strong recommendation.