Conservative approach is usually the first choice for the management of the knee degeneration processes, especially in the phase of the disease recognized as early osteoarthritis (OA) with no clear lesions or associated abnormalities requiring to be addressed surgically. A wide spectrum of treatments is available, from non-pharmacological modalities to dietary supplements and pharmacological therapies, as well as minimally invasive procedures involving injections of various substances aiming to restore joint homeostasis and provide clinical improvement and possibly a disease-modifying effect. Numerous pharmaceuticals have been proposed, but since no therapy has shown all the characteristic of an ideal treatment, and side effects have been reported at both systemic and local level, the use of pharmacological agents should be considered with caution by assessing the risk/benefit ratio of the drugs prescribed. Both patients and physicians should have realistic outcome goals in pharmacological treatment, which should be considered together with other conservative measures. A combination of these therapeutic options is a more preferable scenario, in particular considering the evidence available for non-pharmacological management. In fact, exercise is an effective conservative approach, even if long-term effectiveness and optimal dose and administration modalities still need to be clarified. Finally, physical therapies are emerging as viable treatment options, and novel biological approaches are under study. Further studies to increase the limited medical evidence on conservative treatments, optimizing results, application modalities, indications, and focusing on early OA will be necessary in the future. Level of evidence IV.