<p>The extracellular matrix (ECM) plays a fundamental role in maintaining skeletal muscle structure and facilitating tissue repair following injury. Alterations in its composition can disrupt regeneration, promote fibrosis, and increase susceptibility to musculoskeletal injury. The aim of this study was to investigate whether the BGN (rs1042103), DCN (rs13312816 and rs516115), ELN (rs2071307), FBN2 (rs331079), MMP1 (rs1799750), MMP10 (rs486055), and MMP12 (rs2276109) polymorphisms, either individually or in combination, are associated with susceptibility to musculoskeletal injury. This study included 142 physically active Caucasian participants with a self-reported history of non-contact musculoskeletal injury and 133 participants without such a history. All the samples were genotyped using real-time polymerase chain reaction (real-time PCR). Associations between genotypes, haplotypes, epistatic interactions, and musculoskeletal injury risk were analysed. A nominally increased risk of musculoskeletal injury was observed in individuals carrying:(i) FBN2 rs331079: GC and CC genotypes(ii) MMP12 rs2276109: GG genotype(iii) BGN rs1042103: AG and AA genotypes(iv) DCN rs516115: AG genotypeConversely, the GG genotype of DCN rs516115 appeared protective compared to AA. No significant associations were found for the remaining polymorphisms or for DCN and MMP haplotypes. An epistatic interaction between DCN (rs13312816) and BGN (rs1042103) was detected. Participants with AG/TT and AA/AT genotype combinations had a higher probability of belonging to the injury group. However, across all analyses, no associations remained statistically significant after Bonferroni correction. Specific genotypes of FBN2, MMP12, BGN, and DCN genotypes showed nominal associations with susceptibility to musculoskeletal injury in a physically active Caucasian population; therefore, these findings should be regarded as exploratory.</p>