Objective To observe the status of antithrombotic drug therapy and its influence on clinical outcome in elderly patients with coronary artery disease (CAD) complicated with atrial fibrillation (AF) and malignant tumor. Methods Elderly patients ≥65 years old who were diagnosed with CAD combined with AF and malignant tumor during hospitalization in Chinese PLA General Hospital from January 2010 to December 2017 were continuously recruited, and their clinical baseline data and condition of oral antithrombotic drug treatment were collected. All of the patients meeting our inclusion criteria were followed up for 1 year, the incidences of major adverse cardiovascular events (MACEs) and major bleeding events [bleeding academic research consortium (BARC) class ≥2]. On this basis, the effects of oral antithrombotic therapy on the above clinical outcomes were analyzed in these patients. SPSS statistics 17.0 was used for data analysis. According to the data type, student′s t test, Mann-Whitney U test or Chi-square test was used for comparison between groups. Multivariate logistic regression model was used for correction to determine the independent prediction ability of antithrombotic drug therapy for efficacy and safety of adverse clinical outcomes. Results A total of 135 elderly patients with CAD complicated with AF and malignant tumor who met the inclusion criteria were enrolled in this study. Acute coronary syndrome (ACS) was diagnosed in 40% of patients (54/135) and stenting was performed in 7.4% (10/135). Breast cancer (17.0%, 23/135) and lung cancer (15.6%, 21/135) accounted for the largest proportion most common. The patients were divided into antithrombotic treatment group (n=71) and non-antithrombotic treatment group (n=64). The antithrombotic treatment group had younger age [(77.4±5.7) vs (80.3±6.8)years] and lower plasma D-dimer level [1.03(0.34,1.42) vs 1.82(0.51,2.43) mg/L], and higher platelet count [(199.9±65.0)×10⁹/L vs (176.7±59.8)×10⁹/L] and larger proportion of administration of proton pump inhibitors [59.2%(42/71) vs 29.7%(19/64)]when compared with the non-antithrombotic treatment group (all P<0.05). In the antithrombotic treatment group, 38.0% (27/71) of patients were treated with oral anticoagulant drugs, 32.4% (23/71) with single antiplatelet agents, and 29.6% (21/71) with dual antiplatelet agents (all aspirin combined with clopidogrel). Logistic regression analysis showed that antithrombotic therapy was an independent protective factor for MACEs in elderly CAD patients with AF and malignant tumor (OR=0.111, 95%CI 0.026-0.473; P<0.05); the risk of bleeding events with BARC≥2 was not significantly different between the two groups (OR=0.724,95%CI 0.059-8.826; P>0.05). Conclusion Antithrombotic therapy significantly reduces the incidence of MACEs and does not increase the risk of bleeding events in elderly CAD patients with AF and malignant tumors. It is necessary to strengthen the individualized antithrombotic therapy for elderly patients with CAD complicated with AF and malignant tumor.