The development of the agro-industrial sector in the Russian Federation is primarily driven by the sustainable growth and advancement of crop production. Research conducted from 2020 to 2022 in conditions of unstable moisture in southern Russia aimed to evaluate the effectiveness of various plant protection systems against diseases affecting winter wheat. The object of the study was the winter wheat variety Yuka, while the subject included chemical fungicides and biological agents. The chemical plant protection systems demonstrated the highest biological effectiveness in reducing the incidence of Fusarium root rot and leaf Septoria. In particular, the methods of treatment showed a significant reduction in disease incidence: 77.6% at the tillering stage and 51.5% at the milk-wax ripeness stage compared to control values, exceeding the results achieved with the integrated protection system. For leaf Septoria, the effectiveness was 82.0% at the stem elongation phase and 76.7% during flowering, also surpassing the integrated approach. The highest grain yield of winter wheat reached 7.59 tons/ha, which is 0.79 tons/ha more than the control. The maximum profit was obtained from the application of the integrated disease management system, totaling 47,472.7 RUB/ha, with a profitability level of 111%. The findings of this research highlight the importance of effective plant protection strategies in enhancing wheat production under challenging agro-climatic conditions.