Hyaluronic acid (HA) intraarticular injection is used in the management of osteoarthritis in veterinary medicine. However, HA oral administration is less common given the scarce currently available scientific evidence. This study was aimed at evaluating the effects of oral HA administration on synovial fluid concentrations of several selected biomarkers in dogs with cranial cruciate ligament (CCL) injury operated on using the tibial tuberosity advancement (TTA) technique. Fifty-five dogs were included in this prospective, randomized, double-blind, clinical study; they were randomly assigned to receive either a placebo (group A; n = 25) or HA (group B; n = 30) orally for 10 weeks. Synovial fluid samples were obtained before surgery, and at 10 weeks postoperatively to measure concentrations of HA, haptoglobin, nitric oxide, and paraoxonase-1. After 10 weeks, group HA showed a significant increase in HA concentration (p = 0.0016) and a significant decrease in PON-1 concentration (p = 0.011) compared to baseline. In conclusion, post-op oral HA administration in canine patients with CCL injury leads to improvements in osteoarthritis biomarkers, namely higher synovial fluid HA concentrations and reduced synovial fluid paraoxonase-1 concentrations. These findings support the bioavailability of orally-administered HA and its usefulness in improving biomarkers of osteoarthritis.