Actinic keratosis (AK) and squamous cell carcinoma (SCC) represent progressive keratinocyte disorders in which oxidative stress and dysregulated signaling contribute to disease pathology. Medical gas plasma is an emerging therapeutic tool that generates reactive oxygen and nitrogen species capable of modulating cellular function. Here, we evaluated a newly developed helium multijet plasma device for its potential to treat precancerous and cancerous keratinocyte diseases. To cover the entire keratinocyte carcinogenesis process, in vitro models of normal keratinocytes (HaCaT), AK (HT-297.T), and SCC (A431) were used. A 2-minute plasma treatment produced moderate levels of reactive species in the liquid phase, inducing intracellular oxidation and decreasing viability in a cell type-dependent manner, being most effective in SCC. Plasma exposure modulated stress- and survival-associated signaling pathways and reshaped the secretion of growth factors and pro-inflammatory chemokines, with AK cells showing the most pronounced responses. These findings demonstrate that plasma-generated oxidants act as signaling mediators that can fine-tune keratinocyte behavior without overt cytotoxicity in vitro , supporting the potential of controlled plasma exposure as a therapeutic strategy for actinic keratosis and other skin cancers.