The topical delivery of chemotherapeutics is a promising approach for the management of skin disorders. However, diverse pharmaceutical strategies are essential to allow penetration of large quantities of drugs to tumor tissue. Herein, an attempt was made to investigate the use of Derma roller® microneedles in combination with doxorubicin HCl (DOX) and celecoxib (CEL) co-loaded liposomes as a potential therapeutic approach for the management of melanoma. DOX/CEL co-loaded liposomes/Gels were prepared and characterized. The results showed that microneedle pretreatment with liposomes gel increased DOX penetration into the skin approximately 2-fold compared with the passive delivery. Both CEL liposomes and DOX liposomes caused significant growth inhibition on B16 cells. Besides, DOX/CEL co-loaded liposome was found more cytotoxic than DOX/CEL solution and single drug loaded liposome. The transdermal delivery of DOX/CEL co-loaded liposome successfully inhibited subcutaneous melanoma in female BALB/nude mice, and the co-administration of DOX/CEL with liposomes was better and significantly enhanced the antitumor effect more than single-drug-loaded liposomes. Furthermore, Dermarollers treatment prior to gel application strongly improved the tumor inhibition rate. DOX/CEL co-loaded liposome delivery via microneedles is a promising strategy for skin tumor treatment with targeting inhibition efficiency and negligible side effects.