Acute monoarthritis, characterized by pain or swelling in a single joint, is a diagnostic challenge in the primary care setting. Intra-articular conditions typically manifest with reduced active and passive range of motion, whereas patients with periarticular conditions such as tendinitis or bursitis often maintain passive range of motion. When evaluating a patient with acute monoarthritis, it is essential to remember that many polyarthritic processes can initially present in a single joint. A broad differential diagnosis for monoarthritis should include septic arthritis, osteoarthritis, gout, trauma, and Lyme arthritis. Of these, septic arthritis is the most urgent and requires prompt intervention. Bacterial culture of the synovial fluid is the most accurate diagnostic test for a septic joint. However, diagnostic accuracy can be increased in the short term by evaluating additional markers such as synovial white blood cell count, synovial lactate, and serum biomarkers. These supplementary tests aid in early decision-making while awaiting bacterial culture results. Osteoarthritis is often clinically diagnosed and may be confirmed with radiography. Gout, the most prevalent crystalline arthropathy, can be diagnosed using specialized calculators, ultrasonography, and dual energy computed tomography. Gout is typically most painful at night or in the early morning. Ultrasonography is useful for identifying effusions in less-visible joints and facilitating precise joint aspiration.