The insights gained from the long-term impacts of tillage and N fertilization on soil fertility are crucial for the development of sustainable cropping systems. The objectives of this study were to quantify the effects of 75 years of tillage and N fertilization on macronutrients in soil and wheat (Triticum aestivum L.) tissues grown in a winter wheat–summer fallow rotation. The experiment included three types of tillage (disc, DP; sweep, SW; and moldboard, MP) and five N application rates (0, 45, 90, 135, and 180 kg ha−1). Soil and tissue samples were analyzed for the concentration of total N, S, and C, Mehlich III extractable P, K, Mg, Ca in the soil, and the total concentration of the same nutrients in wheat tissue. Soil N concentration was significantly greater under DP (1.10 g kg−1) than under MP (1.03 g kg−1). The P concentration in upper 20 cm soil depth increased with increased N rates. Comparison of experiment plots to a nearby undisturbed pasture revealed a decline of P (32%), SOC (34%), Mg (77%), and Ca (86%) in the top 10 cm soil depth. The results suggest that DP with high N rates could reduce the macronutrient decline in soil and plant over time.