Abstract: Determining the optimal nitrogen (N) rate in corn remains a critical issue, mainly due to unaccounted spatial (e.g., soil properties) and temporal (e.g., weather) variability. Unmanned aerial vehicles (UAVs) equipped with multispectral sensors may provide opportunities to improve N management by the timely informing of spatially variable, in-season N applications. Here, we developed a practical decision support system (DSS) to translate spatial field characteristics and normalized difference red edge (NDRE) values into an in-season N application recommendation. On-farm strip-trials were established at three sites over two years to compare farmer’s traditional N management to a split-application N management guided by our UAV sensor-based DSS. The proposed systems increased nitrogen use efficiency 18.3 ± 6.1 kg grain kg N?1 by reducing N rates by 31 ± 6.3 kg N ha?1 with no yield differences compared to the farmers’ traditional management. We identify five avenues for further improvement of the proposed DSS: definition of the initial base N rate, estimation of inputs for sensor algorithms, management zone delineation, high-resolution image normalization approach, and the threshold for triggering N application. Two virtual reference (VR) methods were compared with the high N (HN) reference strip method for normalizing high-resolution sensor data. The VR methods resulted in significantly lower sufficiency index values than those generated by the HN reference, resulting in N fertilization recommendations that were 31.4 ± 10.3 kg ha?1 higher than the HN reference N fertilization recommendation. The use of small HN reference blocks in contrasting management zones may be more appropriate to translate field-scale, high-resolution imagery into in-season N recommendations. In view of a growing interest in using UAVs in commercial fields and the need to improve crop NUE, further work is needed to refine approaches for translating imagery into in-season N recommendations.