Background: Next-generation 5G communication technology involves increasing use of 3–100 GHz wireless bands in population centers. Though still non-ionizing, this implies higher radiation energy vs. existing bands. The range is also shorter, needing more numerous emitters, closer to the user—resulting in higher electromagnetic energy exposure. With no universal consensus regarding exposure risks, there is some concern among the public and the scientific community, following indications that 5G radiation can impact immune function, trigger inflammatory responses, and influence expression of genes affecting protein folding, oxidative stress, tissue/extracellular matrix (ECM) matrix turnover, and more. This work aims at identifying botanical extracts for protection of human skin from these impacts, based on a preliminary cell culture-based model. Methods: We irradiated human epidermal keratinocytes at 6 GHz, evaluating effects on Interleukin1-\alpha (IL1-\alpha), a key inflammatory cytokine; TIMP metallopeptidase inhibitor 1 (TIMP1), shown to inhibit collagenase; Angiopoietin-like protein 4 (ANGPLT4), which plays a role in wound healing and epidermal differentiation; and S100 calcium-binding protein A9 (S100A9), involved in immune recruitment during injury, by enzyme-linked immunosorbent assay (ELISA) and immunostaining. We next used this model to identify substances able to mitigate the effects of 5G irradiation, through the evaluation of the influence of treatment by one of several botanical extracts on the observed effects of 5G irradiation. Results: After a remarkably short 1-h exposure, clear effects on keratinocyte function were observed: increased inflammatory cytokine IL1-\alpha; reduced collagenase inhibitor TIMP1; increased wound healing/differentiation facilitator ANGPLT4; and increased SA100A9, involved in immune recruitment during injury. On this basis, we then showed the protective effects of selected botanical extracts, capable of reducing the increase in IL1-\alpha induced by 5G exposure, possibly in part due to anti-inflammatory and anti-oxidant properties of compounds present in these extracts. Conclusions: Our results show a clear influence of 5G irradiation on the keratinocytes, possibly indicating injury and damage responses. What’s more, we showed how these preliminary data can be used to identify botanical extracts capable of offering some protection against these effects for users of 5G technology, e.g., when employed as active ingredients in protective cosmetic applications.