Purpose: To investigate the effect of combining aspirin with clopidogrel on high-sensitivity C-reactive protein (hs-CRP) and P-selectin in patients with acute coronary syndrome (ACS). Methods: The medical records of 198 ACS patients treated at Zhaotong Traditional Chinese Medicine Hospital, Zhaotong, China between January 2022 and January 2023 were analyzed retrospectively. Control group (88 patients) received aspirin (300 mg once, and subsequently a maintenance dose of 100 mg daily for 6 months), while the study group (118 patients) received the same dose of aspirin and clopidogrel (150 mg once, and a maintenance dose of 75 mg daily for 6 months). Levels of P-selectin, interleukin-6 (IL-6), hs-CRP, IL-8, tumor necrosis factor-α (TNF-α), efficacy, and incidence of adverse reactions in both groups were determined. Results: There was no significant difference in P-selectin and hs-CRP levels between the two groups before treatment (p > 0.05). However, P-selectin and hs-CRP levels in the study group decreased significantly compared to control group (p < 0.0001). Similarly, there was no significant difference in IL-8, IL-6 and TNF-α levels between the two groups before treatment (p > 0.05). However, IL-8, IL-6, and TNF-α reduced significantly after treatment (p < 0.0001), with more significantly lower levels observed in the study group (p < 0.001). There was no significant difference in the incidence of adverse reactions between the two groups. Conclusion: Aspirin combined with clopidogrel significantly lowers P- selectin, and hs-CRP, IL-8, IL-6, and TNF-α levels without worsening adverse reactions. A more comprehensive analysis of the combined use of aspirin with clopidogrel including all the associated mechanisms in the treatment of ACS is necessary.