The deployment of novel technologies in the field of precision farming has risen to the top of global agendas in response to the impact of climate change and the possible shortage of resources such as water and fertilizers. The present research addresses the performance of water and nitrogen-sensitive narrow-band vegetation indices to evaluate the response of sweet maize (Zea mays var. saccharata L.) to different irrigation and nitrogen regimes. The experiment was carried out in Valenzano, Bari (Southern Italy), during the 2020 growing season. Three irrigation regimes (full irrigation, deficit irrigation, and rainfed) and two nitrogen levels (300 and 50 kg ha⁻¹) were tested. During the growing season, a Field Spec Handheld 2 spectroradiometer operating in the range of 325–1075 nm was utilized to capture spectral data regularly. In addition, soil water content, biometric parameters, and physiological parameters were measured. The DATT index, based on near-infrared and red-edge wavelengths, performed better than other indices in explaining the variation in chlorophyll content, whereas the double difference index (DD) showed the greatest correlation with the leaf–gas exchange. The modified normalized difference vegetation index (NNDVI) and the ratio of water band index to normalized difference vegetation index (WBI/NDVI) showed the highest capacity to distinguish the interaction of irrigation x nitrogen, while the best discriminating capability of these indices was under a low nitrogen level. Moreover, red-edge-based indices had higher sensitivity to nitrogen levels compared to the structural and water band indices. Our study highlighted that it is critical to choose proper narrow-band vegetation indices to monitor the plant eco-physiological response to water and nitrogen stresses.