Osteoarthritis (OA) is one of the most common musculoskeletal diseases and highly prevalent in older people. Whilst the management of knee OA is usually multidisciplinary, the use of comprehensive geriatric assessment (CGA) for this condition is still limited. Given this background, with this systematic review, we summarized the current literature regarding the importance of CGA in people affected by knee OA. A systematic search across several databases was run until 10th April 2022 and updated on 21st November 2022 for any study investigating the use of CGA in patients with knee OA. The data were summarized descriptively. Among 295 articles initially included, three studies made in the context of the osteoarthritis initiative (OAI) were included. All the three studies used the OAI multidimensional prognostic index (MPI), a composite score derived from the CGA. Higher MPI values were associated with a higher risk of falls, cardiovascular conditions, and fractures across a follow-up period of 8 years and after adjusting for potential confounders. In conclusion, in this systematic review we summarized the current evidence of CGA in knee OA, finding that the MPI, a CGA derived tool, could be useful to early find people at higher risk of conditions that are associated with knee OA and therefore that can be the target of personalized interventions for preventing these conditions.