Cotton is a global cash crop with a significant contribution in the world economy. Optimum nutrient and water supply are most important for sustainable cotton production under warmer and dry environments. Field experiments were carried out to evaluate the cumulative impacts of various nitrogen doses and mulches on sustainable cotton production under semi-arid conditions during 2018 and 2019. Four nitrogen doses; 0, 70, 140, and 210 kg ha−1 and three types of mulch: control (without mulch), natural mulch (5 tons/ha wheat straw), and chemical mulch (methanol (30%). Nitrogen 210 kg ha−1 with natural mulching increased 40.5% gunning out turn, 30.0% fiber length, 31.7% fiber strength, 32.6% fiber fineness, 20.8% fiber uniformity, and 34.0% fiber elongation. Shoot nitrogen, phosphorous, potassium, calcium, and magnesium contents were maximum where 210 kg ha−1 nitrogen and mulch was applied. Natural mulch reduced the soil temperature as compared to chemical and no mulch conditions. The soil temperature was 0.5 to 1.8 ℃ lower in mulching treatments as compared to the control. Maximum economic yield was around 90% higher in natural mulch with the 210 kg ha−1 nitrogen application. It is concluded that optimum nitrogen application with natural mulch not only enhanced plant growth and development but also induced sustainability in quality cotton production under semi-arid conditions.