Lynch syndrome carriers face a high cancer risk, especially colorectal cancer. Although physical activity is known to reduce cancer risk in Lynch syndrome, it remains unclear whether this protective effect varies by sex and which molecular mechanisms underlie it. This study aimed to use an integrated omics approach to examine molecular mechanisms associated with physical activity in Lynch syndrome, focusing on sex-specific differences and links to cancer-related processes. We profiled serum sample-based circulating microRNAs by Illumina sequencing and quantified metabolites using targeted NMR-based metabolomics from 93 Finnish Lynch syndrome carriers. Physical activity levels were assessed by questionnaire. Bioinformatics approaches, e.g. Principal Coordinates analysis (PCoA), Weighted Correlation Network Analysis (WGCNA), and Over-representation Analysis (ORA), identified molecular mechanisms associated with physical activity and links to cancer-related mechanisms. In addition, a short submaximal exercise bout was conducted to examine acute microRNA responses. We observed sex-based differences in physical activity-associated circulating microRNAs and metabolites. In females, physical activity was linked to lipid metabolism. In males, microRNAs negatively correlated with physical activity are associated with distinct cancers, regulating pathways involved in cell growth, apoptosis, transcription, senescence, and the cell cycle. Four physical activity-associated microRNAs (hsa-miR-885-3p, hsa-miR-483-5p, hsa-miR-374a-5p, hsa-miR-301a-3p) strongly correlated with metabolites related to lipid and fatty acid metabolism and inflammation, with correlation patterns differing by sex. Expression of these microRNAs changed after acute exercise. Our findings highlight the importance of considering sex as a biological factor in physical activity-based cancer prevention strategies for Lynch syndrome and provide novel insights into underlying molecular mechanisms.