Cold　atmospheric　plasma　(CAP)　has　attracted　increasing　attention　due　to　its　anti-bacterial　and　anti-tumor　effects.　Melanoma　is　an　aggressive　malignancy　with　increasing　incidence　rate　and　poor　prognosis.　Evaluating　cell　viability,　apoptosis　rate　and　reactive　species　injection　efficiency　of　melanoma　cells　and　human　keratinocyte　cells　(HaCaT)　treated　with　CAP　to　analyze　biological　safety　of　CAP.　RNA-sequencing　(RNA-seq)　of　A875　cells　before　and　after　treatment　was　performed　to　further　explore　the　anti-tumor　mechanism　of　CAP.　CAP　had　a　more　significant　biological　effect　on　melanoma　cells　than　HaCaT　cells　by　inhibiting　proliferation　and　promoting　apoptosis.　RNA-sequencing　analysis　showed　that　besides　MAPK　and　p53　apoptotic　signaling　pathways,　necroptosis　and　autophagy　also　played　important　roles　in　CAP-induced　melanoma　cells　death.　CAP　can　selectively　kill　melanoma　cells　and　has　good　biosafety　cytologically.　Besides　apoptosis,　CAP　can　induce　cell　death　via　autophagy　and　necroptosis.