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Post-acute sequelae of SARS-CoV-2 infection (PASC) frequently includes persistent fatigue and cognitive dysfunction, but the relationship between these symptoms remains poorly defined. In this prospective observational study at the Henry Ford St. John Long COVID Clinic (LCC) from July 2023 to March 2025, we assessed fatigue severity using the Fatigue Assessment Scale (FAS) and examined its relationship with depression and cognitive symptoms. New patients completed demographic and clinical questionnaires, Patient Health Questionnaire (PHQ)-9, and Montreal Cognitive Assessment (MoCA) at their first LCC visit. Among 41 patients, 35 (85.4%) met the inclusion criteria for fatigue (FAS ≥ 22), with 18 (51.5%) experiencing severe fatigue (FAS > 34). Severe fatigue was significantly associated with shortness of breath, chest pain, and depression. Patients experiencing severe fatigue had significantly higher median PHQ-9 scores (12.5) compared to those with mild to moderate fatigue (5.0, p < 0.001). However, there were no significant differences in MoCA scores between these groups. Our study suggests a strong relationship between fatigue and depression in patients with PASC, emphasizing the importance of integrated physical and psychological healthcare. Moreover, since cognitive performance does not vary with fatigue levels, all PASC patients with cognitive dysfunction should receive routine cognitive screenings, regardless of the severity of their fatigue.