This study investigated chronic changes in cell free DNA (cf-DNA) and other biochemical markers throughout a college soccer season. Twenty three NCAA Division I male collegiate soccer players volunteered to participate in this study. Athletes were divided into two groups based upon their weekly average game time rating of session rating of perceived exertion (sRPE). Group 1 (G1, n = 13, age 21.7 ± 1.5 years, height 178.8 ± 6.9 cm, body mass 77.9 ± 6.5 kg), consisted mostly of starters, averaged greater than a weekly 1500 game time sRPE over a fifteen week Fall season. Group 2 (G2, n =10, age 20.6 ± 1.0 years, height 181.8 ± 7.4 cm, body mass 82.5 ± 10.5 kg) averaged less than 1500 game time sRPE. Venous blood samples were taken three times; preseason, approximately midseason and postseason. In G1, cf-DNA (P = 0.001), CRP (P = 0.000), CK (P = 0.003), cf-DNA %∆ (P = 0.002), CRP %∆ (P = 0.002), CK %∆ (P = 0.002) were all significantly higher than T1 at T2 and T3. In G2, CRP %∆ (P = 0.039) was significantly higher at T2 than T1. Despite the lack of statistically significant differences across all three testing times, cf-DNA %∆, CRP %∆ and CK %∆ increased throughout the season in G1. In G2, cf-DNA %∆, CRP %∆ and CK %∆ were all higher at T2 and T3 than T1 but fewer significant differences were present. This may suggest that cf-DNA is a useful marker to reflect accumulated soccer training and competitive stressors.