The need to better exploit crop yield potential through agronomic practices is driven by the necessity to feed a growing population in a changing climate. In this regard, cereals, including barley, represent strategic crops. Barley grain yield in Poland is comparable to the European average. Under good habitat and agronomic conditions, it can exceed the average. The effects of cropping system (continuous cropping, CC; crop rotation, CR), cultivar (Radek, Skald), plant protection level (control treatment, CT; herbicide, H; herbicide and fungicide, HF), and the interactions among these factors on spring barley yield were evaluated in northeast Poland in 2017–2022. Growing spring barley in the CR system promoted higher yields compared to the CC system due to increased spike density and 1000-grain weight (TGW). Skald, with a higher TGW, yielded more than Radek. H treatment increased barley yield by improving the spike density and TGW, while fungicide inclusion (HF) contributed to further yield increase by improving the TGW. The interaction of CR and HF practices contributed to the greatest realization of the yield potential of both cultivars. The study confirmed the strong contribution of inter-annual weather variability in modifying the effects of cropping system, cultivar, and plant protection strategy on barley yield.