Background Inflammation and metabolic disorders are closely associated with cancer. Whether inflammation leads to metabolic disorders or vice versa during cancer initiation remains unclear. In this study, we explored this temporal relationship and the co-exposure effect on cancer risk. Methods This prospective study had two phases. Initially, we examined the temporal relationship between inflammation (high-sensitivity C-reactive protein (CRP)) and metabolic disorders (metabolic syndrome severity Z -score (MetS-Z)) using a 3.98-year survey and cross-lagged analysis. Subsequently, we assessed the connection of co-exposure to inflammation and metabolic disorders, and the risks of overall cancer, as well as specific obesity-related, non-obesity-related, digestive system, lung, and other cancers using an 11.04-year survey and Cox proportional hazard models. Results The cross-lagged analysis revealed that the path coefficient from baseline CRP to follow-up MetS-Z (beta 2=0.032; 95% confidence interval (CI) = 0.026, 0.046) was more significant than the path coefficient from baseline MetS-Z to follow-up CRP (beta 1=0.009; 95% CI=-0.001, 0.019). During the follow-up, 2304 cases of cancer occurred. Compared with the risk of cancer of patients with low average cumulative CRP and MetS-Z, patients with high value had a significantly increased risk (hazard ratio = 1.54, 95% CI = 1.30, 1.83). The mediation analysis showed that MetS-Z mediated the association between CRP levels and overall cancer (12.67%), digestive system cancer (10.16%), and obesity-related cancer risk (13.87%). Conclusions Inflammation had a greater impact on metabolic disorders than vice versa. Co-exposure to inflammation and metabolic disorders significantly increased the risk of cancer, particularly digestive system and obesity-related cancers. Registration Chinese Clinical Trial Registry: ChiCTR- TNRC-11001489.