Background. Human papillomavirus (HPV) is a self-limiting disease, and there is no specific antiviral drug at present. Purpose. Here, we analyzed the influence of lacidophilin vaginal capsules plus recombinant human interferon α-2b (rh-IFN-α2b) on efficacy, vaginal microecology, and safety of patients with HPV infection. Two hundred cases of HPV infection admitted between January 2019 and December 2020 were retrospectively collected. Of them, 90 cases receiving rh-IFN-α2b intervention were assigned to the control group (CG), and 110 cases given lacidophilin vaginal capsules in addition to rh-IFN-α2b were included in the research group (RG). Baseline data, efficacy, vaginal microecology, microecological restoration recovery, and incidence of adverse events (AEs) were compared between the two groups. Results. The analyses revealed nonsignificant difference in baseline data between RG and CG, indicating comparability. In terms of efficacy, RG showed a statistically higher negative conversion ratio (NCR) than CG (57.27% vs. 47.78%), as well as an obviously higher overall response rate (ORR) (90.90% vs. 72.22%). As far as the vaginal microecology was concerned, the incidence rates of catalase-positive, sialidase-positive, abnormal microbial density, and abnormal microbial diversity of RG were significantly lower compared with CG, but no evident differences were determined in Trichomonas vaginalis-positive and Candida-positive. As for microecological restoration, RG had an obviously higher vaginal microecological recovery rate than CG (90.00% vs. 65.56%), as well as notably lower vaginal secretion pH and Nugent score. On the other hand, RG and CG showed no statistical significance in the incidence of AEs (12.73% vs. 13.33%). Conclusions. The main contributions of this study are as follows: first, it is confirmed that lacidophilin vaginal capsules plus rh-IFN-α2b has better clinical effects than rh-IFN-α2b alone in HPV-infected patients; second, it demonstrates that the combination therapy can significantly improve NCR and ORR, without increasing the incidence of AEs, and is beneficial to improve patients’ vaginal microecology and promote its restoration from the multidimensional aspects of efficacy, safety, and vaginal microecology and its recovery. Our findings provide valuable clinical evidence for the drug treatment of HPV-infected patients.