Background <p>Lung cancer remains the leading cause of cancer-related deaths globally. Emerging evidence indicates a potential link between blood cell perturbation responses and various diseases. Further investigation into the connection between these responses and lung cancer could provide valuable insights into its biological behavior and improve strategies for risk stratification.</p> Methods <p>This study employs two-sample mendelian randomization, incorporating lung cancer data from the IEU OpenGWAS project, as well as hematopoietic perturbation response data, to investigate the causal relationships between hematopoietic perturbation responses and lung cancer. This study also differentiated between subtypes: small cell lung carcinoma, adenocarcinoma, and squamous cell carcinoma. The primary analytical method was the inverse variance weighted (IVW) approach. Egger intercept analysis, abnormal MR-PRESSO test, Cochran Q, and leave one out analysis were also employed as multiple sensitivity analyses to assess the robustness of the results.</p> Results <p>18 blood cell perturbation responses were significantly associated with lung cancer and its subtypes, including 10 protective factors and 8 risk factors. In addition, reverse Mendelian randomization analysis identified 12 blood cells with reverse causal relationships with cancer, comprising 11 inhibitory factors and 1 promoting factor.</p> Conclusions <p>Our findings demonstrate a potential causal relationship between lung cancer and blood cell perturbation responses, providing a new perspective for diagnosing and treating lung cancer. However, further studies are needed to elucidate the underlying mechanisms.</p>