BACKGROUND: There is strong evidence showing the association between obesity, type 2 diabetes mellitus (T2DM), and knee pain resulting from osteoarthritis. Regular exercise has been reported as a foundational piece of the preventive therapy puzzle for knee osteoarthritis (KOA) patients. Nonetheless, evidence-based exercise protocols for people with comorbidities, such as obesity, T2DM, and KOA are limited. Therefore, the present trial aimed to assess the effectiveness of a 12-week home-based circuit training (HBCT) protocol on various indices related to cardiometabolic health, musculoskeletal fitness, and health-related quality of life (HRQoL) among overweight/obese older adult patients with KOA and T2DM during the COVID-19 lockdown. METHODS: This is a randomized controlled trial study registered at the National Medical Research Register (ID: RSCH ID-21-01180-KGTNMRR ID-21-02367-FUM) and obtained approval on December 9, 2021. Seventy overweight or obese patients with KOA and T2DM (62.2 ± 6.1 years; 56% female) were randomly assigned to the intervention group (n = 35, HBCT) or the no-exercise control group (n = 35, CON). HBCT performed a 12-week progressive protocol (seven exercises; 15-30 repetitions per exercise, 1 min passive rest between exercises; 2-4 rounds per session; 20-60 min total session duration). Blood samples were collected, and assays were performed to assess the lipid profile, liver function, and fasting blood glucose (FBG). In addition, the 30-s Chair Stand Test (30CST) was used to evaluate lower body muscular strength and endurance while the Timed Up and Go (TUG) test was used to evaluate lower limb function, mobility, and the risk of falls for all the participants. HRQoL was assessed using the Osteoarthritis Knee and Hip Quality of Life (OAKHQoL). All the assessments were conducted at pre-, mid-, and post-training stages during the application or practice of the exercise protocol, rather than during the training sessions themselves. RESULTS: HBCT significantly reduced total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), aminotransferase, alanine aminotransferase, FBG and knee pain (p < 0.05). Furthermore, HBCT induced meaningful increases in high-density lipoprotein (HDL-C), lower body muscular strength, endurance, function, mobility, and HRQoL in overweight/obese older adults with T2DM and KOA (p < 0.05). CONCLUSION: The present outcomes recommend that an injury-free HBCT program may improve various indicators related to cardiometabolic health, musculoskeletal fitness, and HRQoL in elderly with overweight/obesity, T2DM and KOA. These findings offer valuable insights for clinicians and practitioners seeking evidence-based exercise interventions tailored for patients managing substantial metabolic and musculoskeletal health challenges in clinical practice.