Winter wheat (Triticum aestivum) is one of Switzerland’s most important field crops and requires large quantities of nitrogen (N) to produce a high yielding and high-quality crop. However, N is an expensive input for producers that is prone to environmental losses, thus causing pollution and environmental degradation. Furthermore, the N use efficiency (NUE) of wheat remains low. Our goals were to test whether different N fertilizer splits could maximize grain yield and grain N content (a proxy for grain quality) while improving nitrogen use efficiency, identify key variables in determining yield and N grain content, and to determine if variety- and site-specific fertilization recommendations provide additional benefits to nutrient use efficiency. We designed a four-year study across three sites in Switzerland that incorporated five top Swiss varieties of winter wheat and six different N application regimes applied at BBCH 21, 31, and/or 39 that totaled either 0, 80, or 160 kg N ha−1. In addition to mixed model analyses, we used random forest to identify key genetic, environmental, and management variables in determining wheat grain yield and grain N content. Grain N content and yield were found to be maximized at 8000 kg ha−1 and ≈ 2.24% N. Further, more N is required to increase grain N content compared to yield. With respect to nitrogen use efficiency, we found that the total amount of N applied has a greater effect on NUE compared to the rate of the N splits. In general, the rate of the first and second N applications were most important in determining both yield and grain N content, but the rate of the third N application was important in determining the latter. In general, our results did not show broad support for variety-specific fertilization, however site-specific fertilization holds some promise. Creating a winter wheat fertilization system that reduces negative environmental externalities while retaining high yields and quality remains challenging. However, we found that under the conditions tested here, a N regime of 40-40-80 kg N ha−1 may maximize both yield and grain N content, and under some circumstances, improve nitrogen utilization efficiency. This may provide environmental benefits, as well as monetary benefits for producers. Given the current focus on nitrogen use and regulation, research maximizing the utility of nitrogen applications to ensure high grain yield, grain N content, and nitrogen use efficiency is vitally important. This and future work will help producers grow high-quality crops while lessening the environmental impact.