Introduction Combining an antiplatelet drug, clopidogrel, with the direct oral Factor Xa inhibitor, apixaban, could provide an effective antithrombotic strategy in dogs. Thus, a limited 3 + 3 phase I dose-escalation clinical trial in healthy dogs was conducted to evaluate bleeding (primary end-point) and pharmacodynamic (PD)/pharmacokinetic (PK) parameters (secondary end-point). Animals Eleven beagle dogs, median body weight 10.2 kg (9.7–10.9 kg), were enrolled. Methods Four doses of apixaban (three dogs/dose) administered for eight days. Clopidogrel dose was fixed at 18.75 mg per os (PO) q 24 h with escalation of apixaban dose at 5 mg PO q 12 h, 5 mg PO q 8 h, 10 mg PO q 12 h, and 10 mg PO q 8 h. Laboratory testing included fecal occult blood, coagulation parameters, Factor X activity, apixaban concentration, platelet aggregometry, and thromboelastography on days 1, 3, and 8. Results Evidence of bleeding was not observed at any dosage. Dose-dependent changes in PD/PK parameters between baseline and 3 h post-medication were observed including a prolongation of prothrombin time, a prolongation of activated partial thromboplastin time, a decrease of Factor X activity level, and increased apixaban concentration. Conclusions The combination of apixaban at a dosage range of approximately 0.5 mg/kg PO q 12 h to 1 mg/kg PO q 8 h and clopidogrel at approximately 1.8 mg/kg PO q 24 h did not cause bleeding over a one-week period in healthy dogs. Clinically relevant changes in PD/PK data occur at all dosage levels. This study provides a starting point for longer-term clinical trials to determine safety and efficacy.