Objective The use of perinatal-derived tissues and mesenchymal stromal cells (MSCs) as alternative treatment options to corticosteroid and hyaluronic acid injections has been gaining popularity. However, their ability to attenuate osteoarthritic (OA) symptoms while also slowing the progression of the disease remains controversial. Thus, the objective of this article is to summarize the results from both preclinical and clinical studies evaluating the efficacy of perinatal-derived tissue allografts and MSCs for the treatment of OA. Design A comprehensive literature search was conducted on databases including Pubmed, ScienceDirect, and Google Scholar beginning in March 2020 for both preclinical and clinical studies evaluating perinatal-derived tissues and MSCs in OA. Eighteen studies met the inclusion criteria and were used for this review. Results Both animal models and early human clinical trials demonstrated that perinatal tissues could reduce joint inflammation and pain as well as improve range of motion and function in OA. Perinatal tissue–derived MSCs in animal studies have shown the potential to support chondrocyte proliferation while also decreasing inflammatory gene and protein expression. Limited clinical results suggest perinatal tissue–derived MSC sources may also be a viable alternative or adjunct to hyaluronic acid in reducing pain and symptoms in an arthritic joint. Conclusions Perinatal tissue–derived allografts and MSCs have promise as potential therapeutics for mitigating OA progression. However, further research is warranted to fully define the therapeutic mechanism(s) of action and safety of these biological therapies.