Since the development of cold atmospheric plasma (CAP), substantial and significant usage of CAP applications was introduced in medicine. Here, we developed two combined sources of plasma to produce in situ plasma‐activated air‐driven water mist (PAAWM). The first is generated using air as a feed gas, while the second is plasma‐activated water generated by the ignition of plasma within the air‐driven water mist. Both contribute to the plasma jet generation of PAAWM. The antitumor efficacy of PAAWM was evaluated against two hepatocellular carcinoma cell lines (SNU‐449 and SNU‐475). The generated PAAWM was efficient in the treatment of both chemosensitive and chemoresistant hepatocellular carcinoma cells. These results may support using PAAWM alone or in combination with other treatment modalities.