Background <p>Portal vein thrombosis (PVT) impairs blood flow and leads to portal hypertension (PH). In children, common causes of PVT include neonatal umbilical vein catheterisation (UVC), sepsis, dehydration, and thrombophilia. In recent years, COVID-19 infection has also been associated with thromboembolic complications in children. This article presents a case of a 15-year-old girl initially suspected of juvenile-onset systemic lupus erythematosus (jSLE), whose symptoms were ultimately identified as a consequence of post-thrombotic hypersplenism.</p> Case presentation <p>The patient was referred to the pediatric rheumatology department with chronic leukopenia and thrombocytopenia, along with headaches and knee joint pain. Due to the aforementioned symptoms and the presence of positive anti-nuclear antibodies (ANA), the initial reason for referral was the suspicion of jSLE. During hospitalisation, the patient was found to have splenomegaly, a post-thrombotic portal vein cavernoma, and signs of collateral circulation. The diagnosis of chronic PVT was confirmed. Highly positive anti-SARS-CoV-2 IgG antibodies were detected, despite no prior COVID-19 vaccination. Following differential diagnostic evaluation, including congenital and acquired thrombophilias, no identifiable cause of PVT was established. Given the evident signs of a prior infection, COVID-19 was postulated as a potential triggering factor for the endured PVT episode.</p> Conclusions <p>In the absence of typical risk factors, the diagnosis of PVT in children may be challenging. Symptoms of chronic PVT can mimic other conditions, including jSLE. Despite the absence of typical acute thrombosis, the contribution of COVID-19 to the development of PVT in the presented case may be considered.</p>