The possible benefits of an atmospheric pressure plasma jet skin treatment have been tested in vivo on mouse skin. Many studies have been conducted in vitro on mouse skin cells, but only a few in vivo where, due to the complexity of the biological system, plasma can cause severe damages. For this reason, we investigated how kHz plasma generated in a jet that is known to inflict skin damage interacts with mouse skin and explored how we can reduce the skin damage. First, the focus was on exploring plasma effects on skin damage formation with different plasma gases and jet inclinations. The results pointed to the perpendicular orientation of a He plasma jet as the most promising condition with the least skin damage. Then, the skin damage caused by a He plasma jet was explored, focusing on damage mitigation with different liquid interfaces applied to the treatment site, adding N2 to the gas mixture, or alternating the gas flow dynamics by elongating the jet's glass orifice with a funnel. All these mitigations proved highly efficient, but the utmost benefits for skin damage reduction were connected to skin temperature reduction, the reduction in reactive oxygen species (ROS), and the increase in reactive nitrogen species (RNS).