Introduction: Multimorbidity clusters have been associated with increased dementia risk. While lifestyle factors may modify dementia risk, their role in multimorbidity clusters remains unclear. Method: Data from UK Biobank was used to identify clusters of chronic conditions using latent class analysis, assess their associations with dementia risk using Cox regression, and potential moderating effects of lifestyle factors. Results: We included 465,175 participants (mean age (SD) = 56.52 (8.01), 53.87 % female). Five clusters were identified and significantly associated with increased dementia risk, with the cardiometabolic (HR = 2.14, p < 0.001) and mental health cluster (HR =1.99, p < 0.001) exhibiting the highest risk. Only moderate physical activity lowered dementia risk in the pain-dominated multimorbidity cluster (HR = 0.77, p = 0.039). Discussion: Lifestyle factors including physical activity may protect against dementia in specific multimorbidity clusters. Future research involving objective and multiple lifestyle measures is needed.