Objective To investigate the risk factors, pathogen distribution, and drug resistance of systemic inflammatory response syndrome (SIRS) after holmium laser ureteroscopic lithotripsy for impacted ureteral calculi (HLULIUC). Patients and Methods The clinical data of 293 patients with HLULIUC in our hospital from October 2017 to February 2021 were retrospectively collected, including age, BMI, stone size, operation time, urine routine, urine culture, basic illness, complete blood count, liver and kidney function, etc. Patients were divided into SIRS and non-SIRS groups according to whether they had SIRS or not. Then the differences in clinical data, blood and urine bacterial culture results, and drug resistance between the two groups were analyzed. Results The incidence of SIRS after HLULIUC was 17.75%. Logistic regression analysis showed that the risk factors of SIRS after HLULIUC include ureteral calculi≥1cm (OR=2.839, 95% CI=1.341–5.647, P=0.021), long operation time (OR=4.534, 95% CI=2.597–12.751, P=0.017), diabetes mellitus (OR=3.137, 95% CI=1.142–7.319, P=0.012), increased preoperative C-reactive protein (OR=1.864, 95% CI=1.05–4.347, P=0.032), and positive urine leukocytes (OR=3.514, 95% CI=1.7237–9.734, P=0.007) and culture (OR=6.034, 95% CI=3.097–15.751, P<0.001) before operation. The main pathogens causing SIRS after HLULIUC were Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Enterococcus faecalis , and Pseudomonas aeruginosa . The pathogenic bacteria are sensitive to drugs including piperacillin/tazobactam, meropenem, tigecycline, teicoplanin, vancomycin, and imipenem. The resistance rates to quinolones (such as levofloxacin) and to the second- and third-generations of cephalosporins were as high as 52.94%–90.19%. Conclusion Ureteral calculi≥1cm, long operation time, diabetes, increased C-reactive protein, and preoperative positive urine leukocytes and culture are independent risk factors of SIRS after HLULIUC. Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Enterococcus faecalis , and Pseudomonas aeruginosa are the main pathogenic bacteria for SIRS after HLULIUC. The pathogenic bacteria are sensitive to drugs, including piperacillin/tazobactam, meropenem, tigecycline, teicoplanin, vancomycin, and imipenem.