In conjunction with cartilage breakdown, muscle maladaptation including atrophy and increased fibrosis have been observed in the quadriceps following anterior cruciate ligament (ACL) injury. Previously observed upregulated muscle-related proteins in the synovial fluid following ACL rupture allude to cellular communication between the joint and muscle. Therefore, the purpose of this study was to determine whether muscle-related analytes are differentially expressed in the serum. Sixteen patients with an acute ACL tear participated in this IRB-approved study. Serum was obtained at two different time points at a mean of 6 and 14 days post-injury, and serum was analyzed by a highly multiplexed assay of 1,300 proteins. Pathway analysis using DAVID was performed; genes included met three criteria: significant change between the two study time points using a paired t test, significant change between the two study time points using a Mann-Whitney non-parametric test, and significant Benjamini post hoc analysis. Twelve analytes significantly increased between time points. Proteins chitinase-3-like protein 1 (p = 0.01), insulin-like growth factor binding protein 1 (p = 0.01), insulin-like growth factor binding protein 5 (p = 0.02), renin (p = 0.004), and lymphotoxin alpha 1: beta 2 (p = 0.03) were significantly upregulated in serum following acute ACL injury. The current results confirm the inflammatory pattern previously seen in the synovial fluid thought to play a role in the progression of post-traumatic osteoarthritis after ACL injury, and this data also provides further insights into important communication between the joint and quadriceps group, whose function is important in long term health.