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Maize (Zea mays L.) is an important cereal crop grown in arid and semiarid regions of the world. During the reproductive phase, it is more frequently exposed to drought stress, resulting in lower grain yield due to oxidative damage. Selenium and zinc oxide nanoparticles possess inherent antioxidant properties that can alleviate drought-induced oxidative stress by the catalytic scavenging of reactive oxygen species, thereby protecting maize photosynthesis and grain yield. However, the effect of zinc selenide quantum dots (ZnSe QDs) under drought stress was not been quantified. Hence, the aim of this study was to quantify the (i) toxicity potential of ZnSe QDs and (ii) drought mitigation potential of ZnSe QDs by assessing the transpiration rate, photosynthetic rate, oxidant production, antioxidant enzyme activity and seed yield of maize under limited soil moisture levels. Toxicity experiments were carried out with 0 mg L−1 to 500 mg L−1 of ZnSe QDs on earthworms and azolla. The results showed that up to 20 mg L−1, the growth rates of earthworms and azolla were not affected. The dry-down experiment was conducted with three treatments: foliar spray of (i) water, (ii) ZnSe QDs (20 mg L−1), and (iii) combined zinc sulfate (10 mg L−1) and sodium selenate (10 mg L−1). ZnSe or Se applications under drying soil reduced the transpiration rate compared to water spray by partially closing the stomata. ZnSe application at 20 mg L−1 at the tasselling stage significantly increased the photosynthetic rate (25%) by increasing catalase (98%) and peroxidase (85%) enzyme activity and decreased the hydrogen peroxide (23%) content compared to water spray, indicating that premature leaf senescence was delayed under rainfed conditions. ZnSe spray increased seed yield (26%) over water spray by increasing the number of seeds cob-1 (42%). The study concluded that foliar application of ZnSe (20 mg L−1) could decrease drought-induced effects in maize.