Background Contrast agents may affect the anticoagulant properties of novel oral anticoagulants. Purpose To evaluate the effect of iohexol as a contrast agent on the anticoagulant activity of oral factor Xa inhibitors. Material and Methods The study included 65 individuals who underwent contrast computed tomography(CT). Group 1 comprised 20 patients using rivaroxaban, Group 2, 20 patients using apixaban, and Group 3, 20 patients using edoxaban. Group 4 was the control group of five healthy volunteers. Iohexol (60 mL) was used as a contrast agent. Blood samples of 2 mL were withdrawn into two tubes at 4 h after the drug dose and 1 h after the contrast CT (CT was performed 3 h after the drug was taken) from all the patients, and for the control group, at any time before and 1 h after contrast CT. The anticoagulant properties of rivaroxaban, apixaban, and edoxaban were evaluated using anti-factor Xa levels. Results The anti-factor Xa level was increased after using the contrast agent in the rivaroxaban group (0.66 ± 0.32 U/mL vs. 0.67 ± 0.32 U/mL; P = 0.01) and the edoxaban group (0.74 ± 0.35 U/mL vs. 0.76 ± 0.36 U/mL; P = 0.006). No significant difference was observed in the apixaban group (0.66 ± 0.33 U/mL vs. 0.66 ± 0.32 U/mL; P = 0.21) and control group (0.02 ± 0.01 U/mL vs. 0.03 ± 0.01 U/mL; P = 0.33). Conclusion The anticoagulant properties of rivaroxaban and edoxaban tended to increase significantly, but there was no statistically significant difference in the anticoagulant properties of apixaban after the administration of contrast agent. To determine whether the small laboratory difference has a clinical effect, there is a need for larger clinical trials (NCT04611386).