Objective <p>To investigate the use of antimicrobials during the perioperative period of minimally invasive coronary artery bypass grafting (MICS CABG) and traditional open-heart bypass grafting. We aimed to determine whether the duration of perioperative antibiotic use and infection rate is significantly different between different surgical methods.</p> Methods <p>A total of 471 cases of coronary artery bypass grafting (CABG) were collected from January 2019 to December 2022. Patients were divided into minimally invasive group (229 cases) and a conventional group (242 cases) according to the type of surgery. We compared differences in the duration of antimicrobial use and infection rates between the two groups.</p> Results <p>Compared with the conventional group, the minimally invasive group had a significantly shorter average duration of antimicrobial therapy [(1.95 ± 2.40) d vs. (4.67 ± 5.89) d, <i>P</i> &lt; 0.001], a higher rate of short antibiotic treatment duration (T ≤ 24&#xa0;h) [51.97% vs. 7.02%, <i>P</i> &lt; 0.001], lower postoperative pneumonia rate [38.86% vs. 56.20%, <i>P</i> &lt; 0.001], lower positive rate of blood and surgical site sample culture (1 case and 0 case) vs. (7 cases and 3 cases), <i>P</i> &lt; 0.001. Subgroup analysis of different durations of antimicrobial treatment (T ≤ 24&#xa0;h, 24&#xa0;h &lt; T ≤ 48&#xa0;h, and 48&#xa0;h &lt; T ≤ 96&#xa0;h) in the minimally invasive group showed that there was no statistically significant difference in the incidence of infection among the various medication durations (<i>P</i> &gt; 0.05).</p> Conclusion <p>Compared with traditional surgery, MICS CABG requires a significantly shorter duration of perioperative antibiotic treatment duration and a reduced incidence of infection. Extending the duration of antibiotic treatment did not reduce the incidence of infection.</p> Trial registration <p>chictr.org.cn ChiCTR2400091571.</p>