This study attempted to investigate the inflammation, oxidative stress, protein expression, pathology variation and pulmonary tumor risk after the exposure of BALB/c mice to zinc oxide nanoparticles (ZnONPs) and nickel nanoparticles (NiNPs) via intratracheal instillation. We observed that lactate dehydrogenase, total protein, caspase-3, 8-hydroxy-2’-deoxyguanosine and p63 were associated with 24-hour exposure to ZnONPs and NiNPs. All the downregulated and upregulated proteins among the 281 proteins and 212 proteins in the 24-hour of ZnONPs and NiNPs exposure were analyzed to evaluate their implications for biological processes and molecular functions. There were 117 proteins upregulation and 164 proteins downregulation after 24-hour of ZnONPs exposure. Furthermore, there were 108 proteins upregulation and 104 proteins downregulation after 24-hour of NiNPs exposure. According to our findings, we suggest employers to reinforce ventilation in the workplace for reducing ZnONPs and NiNPs esxposure. We also suggest that employers must educate employees to use respiratory protector properly and provide respiratory protector for employees to use.