Selenium nanoparticles (SeNPs) are widely used in the fields such as materials, food, and agriculture, due to their large specific surface area, antioxidant properties, and antibacterial capabilities. In this study, SeNPs were synthesized via the mediation by a hot watermelon peel leaching solution. The formation of SeNPs was confirmed and their apparent characteristics were analyzed using scanning electron microscopy, Raman spectroscopy, X-ray diffraction, and Fourier transform infrared spectroscopy (FT-IR). The antioxidant activity of the SeNPs was evaluated by measuring their scavenging capacities for ABTS+ and DPPH free radicals. The findings revealed that the SeNPs synthesized via the mediation by the hot watermelon peel leaching solution were spherical granular with an average particle size of 211.4 nm, and a selenium content of 22.66% as determined by energy dispersive X-ray spectroscopy. The X-ray diffraction pattern lacked sharp Bragg reflections, indicating that the SeNPs were amorphous. FT-IR spectroscopy analysis indicated the presence of substances such as macromolecular proteins, phenols, alcohols on the surface of the SeNPs, which might contribute to their stability and dispersion. Additionally, the results of antioxidant activity tests demonstrated that at a mass concentration of 500 μg/mL, the SeNPs exhibited free radical scavenging rates of 83.80% for ABTS+ and 94.34% for DPPH. In conclusion, spherical SeNPs with an average particle size of 211.4 nm and notable antioxidant activity were successfully synthesized through the mediation by the hot watermelon peel leaching solution. This research provides a theoretical reference for the biosynthesis of SeNPs and application of their antioxidant properties.