We evaluated the impact of weather and fertilization treatments (Control, PK, NPK1, NPK2, and NPK3) on winter wheat grain yields in a long-term trial in Ivanovice, Czech Republic, established in 1956. A total of 15 seasons were evaluated. The mean, maximal, and minimal temperatures in Ivanovice have been significantly increasing since 1961, with annual increases of 0.04 °C, 0.03 °C, and 0.05 °C, respectively. Precipitation has been decreasing annually by −0.54 mm (trend is insignificant). Four significant correlations between weather and grain yield were recorded. There were positive correlations between mean (r = 0.7) and minimal (r = 0.5) temperatures in November and negative correlations between mean temperatures in May (r = −0.6) and June (r = −0.6). The combination of naturally fertile chernozem soil and a beneficial preceding crop (alfalfa) enables sustainable cultivation of wheat, even without mineral fertilizers. The application of mineral nitrogen (N) significantly increases wheat grain yield and yield stability. Without mineral N or with high doses of mineral N, yield stability decreases. According to two response models (quadratic and quadratic-plateau), a reasonable dose of fertilizer is 107 kg ha−1 N for modern wheat varieties, corresponding to a yield of 8.1 t ha−1.