The non-vitamin K antagonist oral anticoagulants (NOACs) exert their anticoagulant effect closely related to their plasma concentrations. Since their distribution volume is related to body weight (and its correlates, i.e., surface area and body mass index, BMI), extremes in body weight may affect their efficacy or safety. Four NOACs are currently available for long-term use, with few exceptions, in atrial fibrillation and venous thromboembolism: the direct thrombin inhibitor dabigatran etexilate, and the factor (F) Xa inhibitors rivaroxaban, apixaban, and edoxaban. Experience in patients with low (<50 kg) or extremely high (>150 kg) body weight is still quite limited, as such patients were rare in registration trials and sometimes directly excluded. In general, increased bleeding and higher mortality rates are observed in patients weighing <50 kg compared with patients weighing 50–100 kg. This may however also be explained by the presence of underlying conditions such as cancer. At the opposite end of the spectrum of body weight, lower antithrombotic efficacy may occur, perhaps due to the dilutional effect of a higher distribution volume. In this article, we review the pertinent literature and analyze the effects of low or high body weight on anticoagulant activity and clinical outcomes of the NOACs, their dose recommendations, and areas of uncertainty.