Several guidelines endorsed the indefinite use warfarin or heparin-containing products for acute venous thromboembolism (VTE) treatment and secondary prevention and discouraged the use of direct oral anticoagulants (DOAC) for patients diagnosed with antiphospholipid syndrome (APS). However, adequate anticoagulation despite warfarin therapy remains a challenge in APS patients. Using DOACs in APS patients is seen in clinical practice, despite the lack of evidence to support their use in this population. In this case series, we aim to evaluate the safety and effectiveness of apixaban use in nine patients with primary or secondary APS at King Abdulaziz Medical City (Riyadh, Saudi Arabia). All patients presented with APS and received apixaban with or without concomitant antiplatelet. Three patients had double positivity, and two patients had triple positivity of antiphospholipid antibodies (aPL). Some patients tolerated apixaban during the follow-up period, but recurrent VTE and stroke were reported in some of them. Bleeding complications were evident in some cases as well. In conclusion, warfarin remains the best choice to prevent VTE recurrence in patients with APS. On the other side, apixaban use in patients with APS may have some safety and effectiveness concerns evidenced by VTE recurrence and bleeding complications. The safety and effectiveness of utilizing apixaban in APS patients need to be assessed in well-controlled randomized trials.