The interpretation of optical canopy sensor readings for determining optimal rates of late-season site-specific nitrogen application to corn (Zea mays L.) can be complicated by spatially variable water sufficiency, which can also affect canopy size and/or pigmentation. In 2017 and 2018, corn following corn and corn following soybeans were subjected to irrigation×nitrogen fertilizer treatments in west central Nebraska, USA, to induce variable water sufficiency and variable nitrogen sufficiency. The vegetation index-sensor combinations investigated were the normalized difference vegetation index (NDVI), the normalized difference red edge index (NDRE), and the reflectance ratio of near infrared minus red edge over near infrared minus red (DATT) using ACS-430 active optical sensors; NDVI using SRSNDVI passive optical sensors; and red brightness and a proprietary index using commercial aerial visible imagery. Among these combinations, NDRE and DATT were found to be the most suitable for assessing nitrogen sufficiency within irrigation levels. While DATT was the least sensitive to variable water sufficiency, DATT still tended to decrease with decreasing water sufficiency in high nitrogen treatments, whereas the effect of water sufficiency on DATT was inconsistent in low nitrogen treatments. A new method of quantifying nitrogen sufficiency while accounting for water sufficiency was proposed and generally provided more consistent improvement over the mere averaging of water effects as compared with the canopy chlorophyll content index method. Further elucidation and better handling of water-nitrogen interactions and confounding are expected to become increasingly important as the complexity, automation, and adoption of sensor-based irrigation and nitrogen management increase