Effusion-synovitis (ES) is recognized as a component of osteoarthritis, creating a need for rapid methods to assess ES on MRI. We describe the development and reliability of an efficient single-slice semi-automated quantitative approach to measure ES. We used two samples from the Osteoarthritis Initiative (OAI): 50 randomly selected OAI participants with radiographic osteoarthritis (i.e., Kellgren–Lawrence (KL) grade 2 or 3) and a subset from the Foundation for the National Institutes of Health Osteoarthritis Biomarker study. An experienced musculoskeletal radiologist trained four non-expert readers to use custom semi-automated software to measure ES on a single axial slice and then read scans blinded to prior assessments. The estimated intraclass correlation coefficient (ICC) for intra-reader reliability of the single-slice ES method in the KL 2–3 sample was 0.96 (95% CI: 0.93, 0.97), and for inter-reader reliability, the ICC was 0.90 (95% CI: 0.87, 0.95). The intra-reader mean absolute difference (MAD) was 35 mm3 (95% CI: 28, 44), and the inter-reader MAD was 61 mm3 (95% CI: 48, 76). Our single-slice quantitative knee ES measurement offers a reliable, valid, and efficient surrogate for multi-slice quantitative and semi-quantitative assessment.