Background: Calcineurin inhibitor (CNI)-based immunosuppression after solid organ transplantation increases the risk of severe COVID-19. Nirmatrelvir/ritonavir, the guideline-preferred oral antiviral in the general population, causes a well-documented, potentially dangerous drug-drug interaction (DDI) with tacrolimus via ritonavir-mediated inhibition of cytochrome P450 3A4 (CYP3A4). Molnupiravir lacks this interaction but remains underused, partly because non-transplant clinicians may not recognize the risk posed by nirmatrelvir/ritonavir or the safety of molnupiravir as an alternative. Methods: We conducted a single-center retrospective analysis evaluating kidney and simultaneous pancreas-kidney (SPK) transplant recipients receiving tacrolimus who completed 61 treatment encounters with molnupiravir (800 mg twice daily for 5 days) for confirmed COVID-19. Tacrolimus trough levels and serum creatinine (SCr) were compared before and after treatment using the Wilcoxon signed-rank test, with Cohen’s d as the effect size estimate. Acute kidney injury (AKI) was classified by KDIGO criteria. Results: Among 52 unique patients, mean tacrolimus trough concentration was unchanged after treatment (pre 5.52 ± 2.26 vs. post 5.47 ± 1.97 ng/mL, mean difference -0.05 ng/mL, 95% CI -0.64 to 0.54; p = 0.941, Cohen’s d = -0.023). Serum creatinine was similarly unchanged (p = 0.706; d = 0.034). Five encounters (8.2%) met KDIGO AKI criteria. None though was attributable to molnupiravir. No adverse effects attributable to molnupiravir were reported, no mortalities, and 1.6% required hospitalization. Conclusions: Molnupiravir showed no evidence of a pharmacokinetic interaction with tacrolimus and no nephrotoxicity in this cohort, supporting its use as the preferred first-line outpatient COVID-19 antiviral for transplant recipients receiving calcineurin inhibitors. Because nirmatrelvir/ritonavir poses a life-threatening interaction risk in this population, primary care providers, emergency physicians, and general nephrologists should default to molnupiravir and consult a transplant pharmacist when uncertain.