The proficient supply of water and nitrogen is a key factor in facility agriculture. In order to pursue high yields, most farmers blindly irrigate and fertilize, leading to yield reduction, quality decline, soil salinization, and fertility destruction. A successive two-year greenhouse experiment was carried out on fruit quality, yield, irrigation water use efficiency (IWUE), and nitrogen use efficiency (NUE) of greenhouse muskmelon (Cucumis melo L.) under drip fertigation, which can provide a scientific basis for local muskmelon intensive production in Southeast China. The experiments were conducted in 2020 and 2021, with three irrigation levels 80% (W1), 100% (W2), and 120% (W3) of ETc and three N levels 60 (N1), 95 (N2), and 130 (N3) kg N ha−1. The amount of drip irrigation water was determined every 5 days based on crop evapotranspiration (ETc). The seasonal irrigation amount ranged from 209.77 mm to 298.86 mm in 2020 and from 201.22 mm to 286.04 mm in 2021. The highest muskmelon yield was obtained in the treatment of W3N3 with an average of 27.38 t ha−1 in 2020 and 27.10 t ha−1 in 2021. Although the yield was improved by increasing nitrogen supply, there was no significant difference between N2 and N3 treatment in two years under the irrigation level of W2 and W3. The highest irrigation water use efficiency was observed in the W1N3 treatment in 2020 and 2021. The NUE increased with decreasing N rates at the same irrigation level. Under the same nitrogen application level, TSS and Vc under low water (W1) were higher than that under medium water (W2) and high water (W3) treatment. The highest content of nitrate in low water and high nitrogen (W1N3) treatment was 55.41 µg/g in 2020 and 52.50 µg/g in 2021, respectively. The yield and quality of muskmelon are often incompatible, for instance, W2N2 treatment can obtain a higher yield, but W1N2 treatment maximizes Vc, TSS of muskmelon quality. Our findings suggest that the irrigation level of 1.0 ETc, nitrogen level of 95 N ha−1, and 3500 kg·ha−1 of decomposed organic fertilizer was recommended as the best combination, which can improve the yield, quality, IWUE, NUE of muskmelon under drip fertigation with soil mulching in the experimental site.