Lung cancer remains the leading cause of death in cancer patients. Severe treatment side effects and late stage of disease at diagnosis continue to be an issue. We investigated whether local treatment using 2-diethylaminoethyl-dextran methyl methacrylate copolymer with p53 (DDMC-p53) with or without cisplatin and/or microwave ablation enhances disease control in BALBC mice. We used a Lewis lung carcinoma cell line to inoculate 140 BALBC mice, which were divided into the following seven groups; control, cisplatin, microwave ablation, DDMC-p53, DDMC-p53 plus cisplatin, DDMC-p53 plus microwave, and DDMC-p53 plus cisplatin plus microwave. Microwave ablation energy was administered at 20 W for 10 minutes. Cisplatin was administered as 1 mL/mg and the DDMC-p53 complex delivered was 0.5 mL. Increased toxicity was observed in the group receiving DDMC-p53 plus cisplatin plus microwave followed by the group receiving DDMC-p53 plus cisplatin. Infection after repeated treatment administration was a major issue. We conclude that a combination of gene therapy using DDMC-p53 with or without cisplatin and microwave is an alternative method for local disease control. However, more experiments are required in a larger model to identify the appropriate dosage profile.