Purpose <p>We aimed to examine the associations between plant-based dietary patterns, genetic risk, proteins, and lung cancer risk.</p> Methods <p>189,541 participants of the UK Biobank were included. The Cox proportional hazards models and restricted cubic splines were performed to assess the associations between overall plant-based diet index(PDI), healthy PDI (hPDI), and unhealthy PDI (uPDI) and lung cancer risk. Polygenic risk score (PRS) was constructed to assess its joint effect with PDIs on lung cancer risk. Mediation analysis was conducted to examine which proteins mediated the associations of PDIs with incident lung cancer.</p> Results <p>Higher PDI was significantly correlated with reduced lung cancer risk(HR:0.90, 95% CI: 0.85–0.96, per SD). An elevated uPDI showed a significant correlation with an increased lung cancer risk(HR:1.08, 95% CI: 1.01–1.15, per SD). Individuals with a combination of high PRS and low PDI (HR: 2.09 [95% CI: 1.48–2.95]) or high uPDI (HR: 1.86 [95% CI: 1.36–2.53]) exhibited a notably higher lung cancer risk compared to those with low PRS and a high PDI or low uPDI. 42 proteins mediated the effect of PDI on lung cancer risk, and the association between uPDI with lung cancer was mediated by 117 proteins. The number of proteins displaying pathway enrichment within the cytokine-cytokine receptor interaction was the highest of the proteins mediated the effect of associations of PDI and uPDI with lung cancer risk.</p> Conclusion <p>A higher PDI correlated with reduced lung cancer risk, while a higher uPDI correlated with an elevated lung cancer risk. Low PDI jointing with high genetic risk increased lung cancer risk. Proteins enriched in cytokine-cytokine receptor interaction may mediate the association between plant-based dietary patterns with lung cancer risk.</p>