Direct oral anticoagulants (DOACs) are generally preferred over warfarin for preventing arterial and venous thromboembolism. However, the efficacy and safety of DOACs in patients with extremely low body weight (BW) are uncertain. This study investigates anti-factor Xa (anti-FXa) activity of apixaban and compares it between patients with normal BW (>50 kg) and underweight (≤50 kg). We enrolled 150 patients on branded generic apixaban (Apixan) for atrial fibrillation (AF), venous thromboembolism, and intracardiac thrombus. Anti-FXa activity of apixaban was measured at peak concentration (C) and trough concentration (C) after at least one week of therapy. Mean age was 64.0 ± 12.7 years, with 53.3% being male. Mean BW was 61.3 ± 15.3 kg. Of the 150 patients, 132 (88%) had AF, and 43 (28.7%) had low BW. Overall, 87.3% and 84.7% of patients had C and C within the expected range. Underweight patients had significantly higher mean C and C than normal BW patients. A higher proportion of low-BW patients exceeded the expected C range compared to normal-BW patients (25.6% vs. 3.7%, < 0.001). Low BW was the only independent predictor of exceeding C specified range (adjusted OR 4.87, 95% CI 1.31-18.15, = 0.018). Most patients maintained apixaban levels within expected ranges, but those with low BW were more likely to exceed the specified range of C.