The left main (LM) coronary artery disease poses high risks for its special anatomical characteristics. Optimal antiplatelet therapy is still controversial in this disease. We aimed to investigate the efficacy and safety of ticagrelor and clopidogrel in patients with stent implantation in the LM coronary artery. We analyzed 3221 patients with stent implantation in the LM coronary artery from January 2011 to June 2022. Patients were separated into two groups: the ticagrelor group (n = 1550) and the clopidogrel group (n = 1671). Baseline data were balanced by propensity score matching. The primary endpoint was all-cause mortality, and secondary endpoints included cardiovascular death, myocardial infarction, stroke, stent thrombosis, or target vessel revascularization. The primary safety endpoint was major bleeding, defined as BARC 3, 5 bleeding. After propensity score matching (n = 1228 in each group), ticagrelor was linked to a lower incidence of all-cause mortality compared with clopidogrel after a three-year follow-up (5.7% vs. 8.5%; HR:0.728; 95%CI:0.537-0.985, P = 0.040). Ticagrelor treatment reduced target lesion revascularization (3.3% vs. 6.4%; HR: 0.542; 95%CI: 0.371-0.791, P = 0.001) and stent thrombosis (1.6% vs. 3.7%; HR: 0.459; 95%CI: 0.271-0.776, P = 0.004). There was no significant difference in major bleeding between the two groups. Multivariate COX analysis suggested that age, heart rate, diabetes, prior myocardial infarction, hemoglobin, serum creatinine, ticagrelor, DAPT duration, LM true-bifurcation, LM stent diameters, and IVUS were independent predictive parameters of all-cause death. Ticagrelor was associated with lower all-cause mortality and no increased risk of major bleeding compared to clopidogrel in LM stenting patients. Thus, ticagrelor can be considered a viable substitute for clopidogrel in LM disease.