BACKGROUND: Micro-photodynamic therapy (MWPDT) combines photo-dynamic (PDT) and microwave-dynamic (MWDT) therapies with sensitizers, offers new avenues for cancer treatment. Despite the fact that novel sensitizers for MWPDT have been successfully synthesized, only a few are being employed effectively. The low tumor-targeting specificity, inability to transport sensitizer's deeper intratumorally, and deteriorating tumor microenvironment all restrict their anti-tumor efficacy. The current work was done aiming at microwave assisted drug delivery of titanium dioxide / rose Bengal conjugated chitosan nanoparticles (TiO/RB@CSNP) for micro- photo-dynamic skin cancer (SKCA) treatment in vitro and in vivo as activated cancer treatment up-to-date modality. MATERIALS AND METHODS: The study was conducted in vitro on human SKCA cells (A-375) and the study protocol application groups in vivo on Swiss albino mice treated with 7,12-dimethylbenz[a]anthracene (DMBA)/croton oil only and were not received any treatment for inducing SKCA, and only after SKCA induction the study treatment protocol began, treatment was daily with TiO/RB@CSNP as MWPDT sensitizer with or without exposure to laser (IRL) or microwave (MW) or a combination of them for 3 min for two weeks. RESULTS: Revealed that CSNP can be employed as effective TiO/RB delivery system that directly targets SKCA cells. Additionally TiO/RB@CSNP is a promising MWPS for and when combined with MWPDT can be very effective in treatment of SKCA-A-375 in vitro (cell viability decreased in a dose-dependent basis, the cell cycle progression in G0/G1 was slowed down, and cell death was induced as evidenced by an increase in the population of Pre-G cells, an increase in early and late apoptosis and necrosis, and an increase in autophagic cell death) and DMBA/croton oil SKCA-induce mice in vivo (induced antiproliferative genes (caspase 3,9, p53, Bax, TNFalpha), suppressed antiapoptotic and antiangiogenic genes (Bcl2,VEGF respectively) effectively reducing the tumors growth and leading to cancer cell death as well as decreased oxidative stress (MDA), and ameliorated enzymatic and non-enzymatic antioxidants (SOD, GR, GPx, GST, CAT, GSH, TAC) as well as renal (urea, creatinine) and hepatic (ALT, AST) functions. This process could be attributed to MWPDT; microwave and/or photo-chemical TiO/RB activation mechanism and antioxidant potential of non activated TiO/RB as well. CONCLUSION: The results indicate that TiO/RB@CSNP has great promise as an innovative, effective delivery system for selective localized treatment of skin cancer that is activated by MWPDT.