The current study was conducted as a prospective, double-blind, randomized trial, involving patients from the clinical routine at the Veterinary Hospital of FCAV UNESP in Jaboticabal, SP. Canine patients diagnosed with cranial cruciate ligament disease and submitted to TPLO were selected and divided into two groups: the Control group (which received an intra-articular placebo) and the Treated group (ADSC-Se, which received an intra-articular enriched secretome of allogeneic mesenchymal stem cells). Parameters evaluated included accelerometry, radiography (to assess bone consolidation and the progression of the post-surgical radiographic osteoarthritis scale), joint ultrasonography (to evaluate joint effusion and articular cartilage characteristics), as well as lameness and joint pain scales, both in the pre-operative and post-operative periods. The data presented herein pertain to both groups, with individual datasets as well as consolidated spreadsheets available for review. Article Abstract: Background: Canine osteoarthritis (OA) secondary to cranial cruciate ligament disease remains progressive even after a surgical intervention with tibial plateau leveling osteotomy (TPLO). Its long-term progression can be severe, and effective therapeutic options are notably lacking to mitigate its progression. This study evaluated the short- and mid-term outcomes of intra-articular allogeneic canine adipose-derived stem cell (ADSC) enriched secretome in dogs undergoing TPLO and its impact on postsurgical OA progression. Methods: A total of 20 client-owned dogs were included and randomly assigned to (n = 10 per group) the control group (CG), which received a placebo intra-articular injection, and the treatment group (ADSC-Se), which received an intra-articular injection of 200–250 µg of ADSC-derived enriched secretome at the end of surgery. The lameness, stifle pain, accelerometry, and OA-related changes via radiography and articular ultrasonography for up to 150 days post-TPLO were examined in both groups. Results: The decrease in lameness and stifle pain was significantly higher in the ADSC-Se group than in the CG (p < 0.05), beginning 15 days postoperatively. However, no statistically significant differences in the accelerometry data were observed between the groups (p > 0.05). Radiographic assessments revealed progressive OA in the CG but decreased in the ADSC-Se group relative to preoperative baselines starting 15 days postoperatively (p < 0.05), maintaining near-normal scores until the end of the study. This demonstrated significant differences between the groups (p < 0.05). Furthermore, the ADSC-Se group showed favorable outcomes (p < 0.05) in ultrasonographic evaluations of joint effusion and articular cartilage integrity, particularly from 30 days postoperatively. Radiographic assessment of bone healing at 30 days post-TPLO was also higher in the ADSC-Se group (p < 0.05). Conclusions: Intra-articular injection of an ADSC-enriched secretome decreases OA progression and facilitates faster clinical recovery in dogs undergoing TPLO.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP: 2022/14243-1