Farmers must adapt to the changes brought about by the changing climate and market requirements. These adaptations are associated with fertilization—the availability of organic manures and mineral fertilizers and crop rotations. What is the effect of organic manures on wheat and soil? Is it necessary to apply mineral phosphorus P and potassium (K) fertilizers to the wheat? These questions are frequently asked in workshops in different growing areas. To provide a relevant answer on this issue, we evaluated how farmyard manure (FYM), mineral nitrogen (N) applied without phosphorus (P) and potassium (K) fertilizers, and application of NPK affected grain yield, grain quality, and soil properties under different soil-climate conditions (Ivanovice—Chernozem, Caslav—Phaeozem, Lukavec—Cambisol) between 2015 and 2018. The FYM significantly increased grain yield even after three years since being applied and incorporated into the soil in all localities, but its application didnot affect grain quality. In the soil, the FYM significantly increased total nitrogen Nt, P, and K content in all localities and oxidable carbon Cox content in two localities. Mineral nitrogen significantly affected grain yield and quality and increased concentrations of soil N and C, but decreased pH in Caslav. Application of mineral P and K wasnot connected with a positive effect on grain yield and quality, but increased the concentration of these elements in the soil, preventing depletion of these elements from the soil. Maximal yields were recorded when 70–98 kg N ha−1 was applied in Ivanovice, 55–72 kg N ha−1 in Caslav, and 155 kg N ha−1 in Lukavec.