Pharmacological treatments are widely recommended in international guidelines for management of osteoarthritis (OA). However, the use of intra-articular (IA) therapies of diverse active drugs remains controversial. We critically reviewed studies of the efficacy and safety of IA injections of corticosteroids (CS), hyaluronic acid (HA), platelet-rich plasma (PRP), and botulinum toxin A (BTA) and evidence-based international recommendations for their use in treating knee OA. The process of article selection was unsystematic. Articles were selected on the basis of authors’ expertise, self-knowledge, and reflective practice. Only studies assessing knee OA were included. IA CS and HA injections were conditionally to fully recommended for treating knee OA. No recommendations have been formulated for IA PRP or BTA. The evidence remains inconsistent and controversial for the use of IA therapies for knee OA. The characteristics of and selection criteria for the OA population that would likely benefit from these therapies need to be identified. Accurately phenotyping and selecting patients is mandatory in future randomized controlled trials. Therefore, efficacy and safety meta-analyses should be performed, as should qualitative and sensitivity analyses of published trial results.