The objectives of this study were to quantify long-term tillage practice and nitrogen (N) fertilizer rate effects on yield and N use in a winter wheat (Triticum aestivum L.)–grain sorghum (Sorghum bicolor L. Moench)–fallow (W–S–F) rotation. The experimental design was a randomized complete block with a split–split-plot arrangement. The main plot treatments were crop rotation phases W–S–F, S–F–W, and F–W–S. The sub-plots were tillage practices, i.e., conventional tillage (CT), reduced tillage (RT), and no-tillage (NT). And the sub-sub-plot treatments were N rates of 0, 45, 90, and 134 kg ha⁻¹. Wheat yield increased at rates of 15.6, 9.3, 22.8, and 25.7 kg ha⁻¹ for a kg N ha⁻¹ increase in very low-, low-, high-, and very high-yielding environments (average yields of ∼2000, 2500, 2800, and 4400 kg ha⁻¹), respectively. On average, winter wheat yields were 7%–9% greater for CT compared with both NT and RT. Winter wheat removed about 52 kg N ha⁻¹ from the unfertilized control treatment, but N uptake varied by N rate and growing conditions. Nitrogen use efficiency, N agronomic efficiency, and applied N recovery decreased as the N rate increased. Across environments, wheat yield increased by 16, 20, and 17 kg ha⁻¹ for each additional kg ha⁻¹ N applied under CT, NT, and RT, respectively, and additional 2–2.5 kg ha⁻¹ yield increases for a mm increase in fallow precipitation. We concluded that wheat yield response to N is highly dependent on growing conditions, and NT required greater N fertilization than CT and RT for similar yields.