Lung cancer remains incurable; therefore, novel therapeutical approaches are ofgreat demand. This study was designed to investigate the effectiveness of cisplatin nanoparticles combined with vitamin-D3 on urethane-induced early lung cancer in rats and to clarify the underlying signaling mechanisms. Early lung cancer was induced in male Wistar rats by urethane. Rats were divided into six groups:I-control, II-cancer untreated, III-cancer + free cisplatin, IV-cancer + cisplatin nanoparticles, V-cancer + free cisplatin + vitamin-D3, VI-cancer + cisplatin nanoparticles + vitamin-D3. Inflammation, proliferation, and apoptosis were evaluated together with the levels of tumor marker CK-19 along with histological assessment. Treatment of lung cancer with either free or nanoparticles of cisplatin alone demonstrated significant suppression in the expression of inflammatory, anti-apoptotic and tumor markers compared to rats with lung cancer. Moreover, vitamin-D3 supplementation with either cisplatin forms lead to a further decrease of all markers, markedly with cisplatin nanoparticles. The presentstudy shows the synergistic effect of cisplatin-nanoparticles combined with vitamin-D3 as a new therapy regimen against lung cancer. Further studies with larger sample sizes and longer duration are needed to confirm these results.