Cold atmospheric plasma (CAP) devices produce reactive oxygen and reactive nitrogen species, which have antimicrobial and antiviral effects, while also affecting the molecular and cellular processes in eukaryotic cells. This study investigates the effects of CAP treatment on immune responses and long-term organism health in the upper respiratory tract (URT). Using a surface-microdischarge-based plasma intensive care (PIC) device from terraplasma medical GmbH, 129Sv/Ev wildtype mice were exposed to short (single 10 min session), long (five 10 min sessions), and recovery-phase treatments (five 10 min sessions; 7 days of recovery). Bronchoalveolar lavage fluid was examined by cytospin, fluorescence-activated cell sorting, and mRNA expression analysis. Lung tissue was analyzed for morphological changes (H&E), DNA damage (γH2AX), apoptosis (TUNEL), immune cell marker alterations (CD45, Ly-6G, CD68, CD3, MCC), and fibrosis (NE). Results showed that PIC treatment increased the number of apoptotic cells and activated immune markers, such as IFN-γ, IL-6, and TNF-α, in the lungs, especially after multiple treatments. These effects largely reversed after a 7-day regeneration period. Importantly, no DNA damage or morphological lung alterations were observed across groups. The findings suggest that PIC treatment in the URT induces transient immune activation without causing tissue damage, but caution is advised for patients with cytokine release syndrome or macrophage activation syndrome due to potential cytokine surges.