Kidney transplantation recipients (KTRs) represent a vulnerable population for COVID-19 infection and severe disease. Nirmatrelvir-ritonavir has demonstrated efficacy in treating COVID-19 among KTRs, which interacts with tacrolimus leading to a precipitous increase in tacrolimus blood levels when co-administered, potentially resulting in toxicity. This study conducted a Real-world analysis of KTRs treated with nirmatrelvir-ritonavir for COVID-19 to investigate the relationship between tacrolimus levels and dosing during and within 10 days post-discontinuation of nirmatrelvir-ritonavir. In the experimental group, patients initiated tacrolimus at 20-25% of the baseline dose 48 hours after discontinuing nirmatrelvir-ritonavir, with daily increments of 20-25% until the baseline dose was restored. Patients who did not adhere to the experimental protocol were included in the control group. Findings indicated that withholding tacrolimus 12 hours prior to commencing nirmatrelvir-ritonavir maintained tacrolimus blood levels above 83% of the baseline throughout the nirmatrelvir-ritonavir treatment period. Compared to the control group, The experimental group achieved target trough concentrations of tacrolimus more rapidly and maintained a higher proportion within the therapeutic range ( p=0.029), and exhibited significantly lower rates of adverse events ( p<0.001). This investigation provides a safe and effective pharmacological strategy for KTRs infected with COVID-19, enabling the safe co-administration of nirmatrelvir-ritonavir and tacrolimus.