Optimizing irrigation and nitrogen (N) fertilizer management in irrigated potato crops grown on sandy soils in subtropical regions such as in northeastern Florida, USA is essential to sustain a high yield and to minimize leaching. N applications in this region typically occur at approximately 25–30 days prior to planting (Npre), at emergence (Neme), and at tuber initiation (Nti). However, recent studies suggest that applying N near planting (Npl) enhances fertilizer N use efficiency (FNUE). We combined experimentation with modeling to assess irrigation and N management options for potato in northeastern Florida. We first aimed to evaluate the DSSAT/CSM-SUBSTOR-Potato model using two-year irrigated field experiments conducted on sandy soils with variable N rates and application timings. CSM-SUBSTOR-Potato accurately simulated aboveground plus tuber dry weight [Relative root mean squared error (RRMSE) = 26.4%, Willmott’s index (d) = 0.98] and N accumulation (RRMSE = 28.6%, d = 0.97). Soil moisture and mineral N were captured well overall, but they were often underestimated due to a water table influence that is currently not considered in DSSAT. Subsequently, CSM-SUBSTOR-Potato was applied to simulate tuber yield, N leaching, and FNUE under scenarios of irrigation scheduling and N-fertilizer application (rate/timing) strategies, focusing on Npre versus Npl aiming to improve resource use efficiency. The simulations indicated that a target of 60% and 70% of the available soil water can be safely used as an irrigation strategy to achieve a high yield, while reducing irrigation water applied and N leached to the environment. Overall Npl increased crop N uptake by 10%, tuber yield by 7%, reduced N leached by 13%, and consequently increasing FNUE by 9%, compared to Npre across the irrigation treatments. Thus, Npl should be preferred in sandy soils and climate-risky subtropical environments, along with Neme and Nti as key timings to synchronize N supply with potato growth.