Nanotechnology has been presenting successful applications in several fields, such as electronics, medicine, energy, and new materials. However, the high cost of investment in facilities, equipment, and materials as well as the lack of some experimental analysis at the nanoscale can limit research in nanotechnology. The implementation of accurate computer models can alleviate this problem. This research investigates the Leidenfrost effect at the nanoscale using molecular dynamics (MDs) simulation. Models of water droplets with diameters of 4 nm and 10 nm were simulated over gold and silicon substrates. To induce the Leidenfrost effect, droplets at 293 K were deposited on heated substrates at 373 K. As a baseline, simulations were run with substrates at room temperature (293 K). Results show that for substrates at 293 K, the 4 nm droplet has higher position variability than the 10 nm droplets. In addition, for substrates at 373 K, the 4 nm droplets have higher velocities than the 10 nm droplets. The wettability of the substrate also influences the Leidenfrost effect. Droplets over the gold substrate, which has hydrophobic characteristics, have higher velocities as compared to droplets over silicon that has a hydrophilic behavior. Moreover, the Leidenfrost effect was observed at the boiling temperature of water (373 K) which is a significantly lower temperature than reported in previous experiments at the microscale. This research lays the foundation for investigating the fluid–structure interaction within several droplet based micro- and nano-manufacturing processes.