Breast cancer (BC) and oral squamous cell carcinoma (OSCC) are among the most common types of cancer, but current clinical outcomes remain unsatisfactory. Available therapies have limitations in terms of efficacy and may also cause severe side effects. Cold physical plasma is a promising approach for selectively eliminating cancer cells while avoiding genotoxic effects on non-malignant cells. In this study, we investigated the potential of cold physical plasma as a therapeutic intervention for BC and OSCC through in vitro and ex vivo studies on toxicity. For the in vitro study, T-47 BC cells and SCC-4 and SCC-9 OSCC cell lines were used, and we found cold plasma to be toxic in a treatment time-dependent manner. Moreover, we investigated the safety of physical plasma therapy and found no genotoxic potential in plasma-treated human keratinocytes in vitro. Finally, for the first time, 20 BC and OSCC patient-derived tumor tissues were punch biopsied and ex vivo-exposed to cold physical plasmas to study responses in the tumor microenvironment TME). Cold physical plasma caused significant apoptosis in patient-derived BC and OSCC tumor tissues, and decreased the number of CD163⁺ cells (e.g., tumor-associated macrophages, TAM) in BC tissue plasma-treated ex vivo. Collectively, our findings motivate the investigation of cold physical plasma as a potential adjuvant treatment in oncology.