Background <p><i>Nocardia brasiliensis</i> is classically associated with localized cutaneous infection and is a rare cause of disseminated disease. Septic arthritis due to <i>Nocardia</i> species is atypical and has rarely been reported without antecedent trauma. We present a case of <i>N. brasiliensis</i> septic arthritis in a patient with active solid organ malignancy.</p> Case presentation <p>An 80-year-old male with non-small cell lung adenocarcinoma, chronic obstructive pulmonary disease, and chronic kidney disease stage 3b presented with refractory soft tissue infections of the left upper and right lower extremities despite prior incision and drainage and oral antibiotics. Hospital course was complicated by progressive right knee effusion. Synovial fluid analysis demonstrated 87,000 white blood cells per microliter, 95% neutrophils, glucose less than 20&#xa0;mg/dL, and no crystals. <i>Nocardia brasiliensis</i> was cultured from multiple noncontiguous sites, including the left upper extremity abscess, right knee synovial fluid, and right lower extremity lesions. Susceptibility testing demonstrated a broad antimicrobial profile but resistance to imipenem and ciprofloxacin. Trimethoprim-sulfamethoxazole and aminoglycosides were relatively contraindicated due to renal function. The patient required right knee arthroscopy with irrigation, debridement, and complete synovectomy, multiple interventional radiology-guided drainages, and prolonged combination antimicrobial therapy with ceftriaxone, linezolid, and minocycline. His course was further complicated by persistent encephalopathy and severe malnutrition requiring enteral nutrition. At the time of reporting, the patient demonstrated clinical improvement of cutaneous and musculoskeletal lesions but remained hospitalized for non-infectious complications.</p> Conclusions <p>This case highlights that <i>Nocardia brasiliensis</i> can cause disseminated musculoskeletal infection including septic arthritis in immunocompromised patients without clear environmental exposure. In patients with chronic kidney disease, standard first-line therapies may be contraindicated, making early species identification and susceptibility-guided therapy essential, particularly given the potential for carbapenem resistance. The central lesson is that empiric carbapenem therapy may fail in <i>N. brasiliensis</i> and that renal impairment narrows treatment options, so timely identification and susceptibility-directed therapy directly determine management, particularly when advanced malignancy further constrains care.</p>