We have previously designed and characterized a 94 GHz exposure system that allows real-time monitoring of subcellular interactions induced by millimeter wave (MMW) stimulation. For example, studies of the calcium dynamics in neuronal cells in response to 94 GHz irradiation suggested that MMW stimulation increased calcium spiking. In this study, we engineered a 3D co-culture model that represents the major constituents of skin. We used this experimental model along with the custom-designed MMW exposure system to investigate the effects of 94 GHz irradiation in the skin-like tissue construct. Unlike typical non-excitable cells, keratinocytes exhibited calcium spikes in their resting state. Exposure to a 94 GHz irradiation induced a statistically significant increase in the calcium spiking. When co-cultured with neuronal cells in the 3D co-culture skin model, changes in the calcium spiking in neuronal cells depended on the MMW input power. Further, the 94 GHz irradiation caused ATP secretion by keratincytes. ATP is a major factor that modulates the calcium spiking in neuronal cells. Surprisingly, while a 5-fold increase in the ATP secretion enhanced the calcium spiking in neuronal cells, a 10-fold increase significantly hindered the calcium dynamics. Computational simulation of ATP-induced calcium dynamics was in general agreement with the experimental findings, suggesting the involvement of the ATP-sensitive purinergic receptors. The engineered co-culture skin model offers a physiologically relevant environment in which the calcium dynamics is regulated both by the cell-MMW and cell-cell interactions.