Importance: Structured education and exercise therapy programs have been proposed to reduce reliance on total knee replacement (TKR) surgery and improve health care sustainability. The long-term cost-effectiveness of these programs is unclear. Objectives: To estimate the lifetime cost-effectiveness of implementing a national structured education and exercise therapy program for individuals with knee osteoarthritis with the option for future TKR compared with usual care (TKR for all). Design, Setting, and Participants: This economic evaluation used a life table model in combination with a Markov model to compare costs and health outcomes of a national education and exercise therapy program vs usual care in the Australian health care system. Subgroup, deterministic, and probabilistic sensitivity analyses were completed. A hypothetical cohort of adults aged 45 to 84 years who would undergo TKR was created. Exposure: Structured education and exercise therapy intervention provided by physiotherapists. The comparator was usual care where all people undergo TKR without accessing the program in the first year. Main Outcomes and Measures: Incremental net monetary benefit (INMB), with an incremental cost-effectiveness ratio threshold of 28033 Australian dollars (A$) per quality-adjusted life-year (QALY) gained, was calculated from a health care perspective. Transition probabilities, costs, and utilities were estimated from national registries and a randomized clinical trial. Results: The hypothetical cohort included 61394 individuals (53.9% female; 93.6% aged ≥55 years). Implementation of an education and exercise therapy program resulted in a lifetime cost savings of A$498307942 (US $339922227), or A$7970 (US $5537) per individual, and resulted in fewer QALYs (0.43 per individual) compared with usual care. At a population level, education and exercise therapy was not cost-effective at the lifetime horizon (INMB, -A$4090 [-US $2841]). Subgroup analysis revealed that the intervention was cost-effective only for the first 9 years and over a lifetime only in individuals with no or mild pain at baseline (INMB, A$11 [US $8]). Results were robust to uncertainty around model inputs. Conclusions and Relevance: In this economic evaluation of structured education and exercise therapy compared with usual care, the intervention was not cost-effective over the lifetime for all patients but was for the first 9 years and for those with minimal pain. These findings point to opportunities to invest early cost savings in additional care or prevention, including targeted implementation to specific subgroups.