The catechol-O-methyltransferase (COMT) is a candidate gene to provide promising evidence of psychiatric disorders, but there is a knowledge gap between the genetic factor and multiple physical activity-related injuries (PARIs). The aim of this study was to explore the contribution of COMT to the risk of PARIs among university students in the Chinese Han population. We can further search for the intrinsic risk factors for the occurrence of multiple physical activity injuries and provide a scientific basis for early screening and precise intervention for the high-risk group of college students with multiple PARIs. A 1:1 matched case-control study of 61 PARIs cases and 61 healthy controls were carried out. DNA samples of the participants were isolated from saliva and genotyped on eight SNPs of the COMT gene (rs9265, rs4680, rs6269, rs4818, rs4633, rs165655, rs165656, and rs165722) using the MALDI-TOF MS method. We found that rs6269 and rs4818 were significantly associated with PARIs, and rs6269-GG and rs4818-GG contributed to the reduced risk of PARIs. Further haplotype analysis showed a four-marker C-G-C-G haplotype (rs165722-rs6269-rs4633-rs4818) acted with a protective role in the development of PARIs (p = 0.037; OR: 0.474, 95% CI: 0.269 to 0.834). However, the interactions between club membership and rs6269 or rs4818 would significantly increase the risk of PARIs (both p < 0.001, OR: 5.121 and 4.977, respectively). This is the first study to find the contribution of COMT to PARIs occurrence, suggesting that the COMT polymorphisms and the gene–environment interactions may alter the risk of PARIs.