Biologics targeting matrix-degrading proteases, cartilage repair, and inflammation are emerging as promising approaches for osteoarthritis (OA) treatment. Recent research highlights biologic-human placental tissue (HPT) as a potential OA therapy due to its biocompatibility, abundant protein biofactors, and ability to reduce cartilage degradation by suppressing protease expression. Microneedles (MNs) are receiving growing attention for enhancing transdermal delivery of biologics as an alternative to conventional subcutaneous injections. The lyophilized human placental extract (LHP) loaded polymeric MNs are fabricated using a micromolding technique for transdermal delivery. Ex vivo release studies reveal that MNs exhibit a gradual and consistent release of LHP, indicating a sustained delivery profile. LHP-MNs are nontoxic and anti-inflammatory in nature against human skin cells and interleukin (IL-1β) induced synovial cells. Furthermore, the in vivo study shows that LHP-MNs substantially improve behavioral parameters in OA rat models and lower serum concentrations of tumor necrosis factor- α (TNF-α) and cartilage oligomeric matrix protein (COMP) biomarkers, thereby alleviating knee and ankle joint injuries. Histopathological analysis indicates that LHP-MNs significantly preserve cartilage integrity. The study results suggest that employing polymeric MNs for transdermal delivery of LHP can be a promising treatment approach for OA, with the added benefit of excellent patient compliance.