We conducted a prospective study to identify genome-wide changes in peripheral gene expression before and after sports-related concussion (SRC). A total of 253 collegiate contact athletes underwent collection of peripheral blood mononuclear cells (PBMCs) before the sport season (baseline). Sixteen athletes who subsequently developed an SRC, along with 16 non-concussed teammate controls, underwent repeat collection of PBMCs within 6 h of injury (acutely). Concussed athletes underwent additional sample collection at 7 days post-injury (sub-acutely). Messenger RNA (mRNA) expression at baseline was compared with mRNA expression acutely and sub-acutely post-SRC. To estimate the contribution of physical exertion to gene changes, baseline samples from athletes who subsequently developed an SRC were compared with samples from uninjured teammate controls collected at the acute time-point. Clinical outcome was determined by changes in post-concussive symptoms, postural stability, and cognition from baseline to the sub-acute time-point. SRC athletes had significant changes in mRNA expression at both the acute and sub-acute time-points. There were no significant expression changes among controls. Acute transcriptional changes centered on interleukins 6 and 12, toll-like receptor 4, and NF-κB. Sub-acute gene expression changes centered on NF-κB, follicle stimulating hormone, chorionic gonadotropin, and protein kinase catalytic subunit. All SRC athletes were clinically back to baseline by Day 7. In conclusion, acute post-SRC transcriptional changes reflect regulation of the innate immune response and the transition to adaptive immunity. By 7 days, transcriptional activity is centered on regulating the hypothalamic-pituitary-adrenal axis. Future efforts to compare expressional changes in fully recovered athletes with those who do not recover from SRC could suggest putative targets for therapeutic intervention.