In addition to managing soilborne diseases, grafting with vigorous rootstocks has been shown to improve yield in tomato (Solanum lycopersicum L.) production. However, the influence of different levels of nitrogen (N) and irrigation supplies on grafted tomato plants has not been fully examined in comparison with non-grafted plants, especially under field conditions. The objective of this two-year study was to determine the effects of different irrigation regimes and N rates on yield, irrigation water use efficiency (iWUE), and N use efficiency (NUE) of grafted tomato plants grown with drip irrigation in sandy soils of north Florida. The determinate tomato cultivar Florida 47 was grafted onto two interspecific hybrid rootstocks, ‘Beaufort’ and ‘Multifort’ (S. lycopersicum × S. habrochaites S. Knapp & D.M. Spooner). Non-grafted ‘Florida 47’ was used as a control. Plants were grown in a fumigated field under 12 combinations of two drip irrigation regimes (50% and 100% of commonly used irrigation regime) and six N rates (56, 112, 168, 224, 280, and 336 kg·ha−1). The field experiments were arranged in a split-plot design with four replications. The whole plots consisted of the irrigation regime and N rate combination treatments, whereas the subplots represented the two grafting treatments and the non-grafted plants. Self-grafted ‘Florida 47’ was also included in the 100% irrigation and 224 kg N/ha fertilization treatment as a control. In 2010, the 50% irrigation regime resulted in higher total and marketable yields than the 100% irrigation regime. Tomato yield was significantly influenced by N rates, but similar yields were achieved at 168 kg·ha−1 and above. Plants grafted onto ‘Beaufort’ and ‘Multifort’ showed an average increase of 27% and 30% in total and marketable fruit yields, respectively, relative to non-grafted plants. In 2011, fruit yields were affected by a significant irrigation by N rate interaction. Grafting significantly increased tomato yields, whereas grafted plants showed greater potential for yield improvement with increasing N rates compared with non-grafted plants. Self-grafting did not affect tomato yields. More fruit per plant and higher average fruit weight as a result of grafting were observed in both years. Grafting with the two rootstocks significantly improved the irrigation water and N use efficiency in tomato production. Results from this study suggested the need for developing irrigation and N fertilization recommendations for grafted tomato production in sandy soils.