Background Oxygen therapy is used in various clinical situation, but its clinical outcomes are inconsistent. The relationship between the fraction of inspired oxygen (F_IO₂) during transcatheter aortic valve implantation (TAVI) and clinical outcomes has not been well studied. We investigated the association of F_IO₂ (low vs. high) and myocardial injury in patients undergoing TAVI. Methods Adults undergoing transfemoral TAVI under general anesthesia were randomly assigned to receive F_IO₂ 0.3 or 0.8 during procedure. The primary outcome was the area under the curve (AUC) for high-sensitivity cardiac troponin I (hs-cTnI) during the first 72 h following TAVI. Secondary outcomes included the AUC for postprocedural creatine kinase-myocardial band (CK-MB), acute kidney injury and recovery, conduction abnormalities, pacemaker implantation, stroke, myocardial infarction, and in-hospital mortality. Results Between October 2017 and April 2022, 72 patients were randomized and 62 were included in the final analysis (n = 31 per group). The median (IQR) AUC for hs-cTnI in the first 72 h was 42.66 (24.82–65.44) and 71.96 (35.38–116.34) h·ng/mL in the F_IO₂ 0.3 and 0.8 groups, respectively (p = 0.066). The AUC for CK-MB in the first 72 h was 257.6 (155.6–322.0) and 342.2 (195.4–485.2) h·ng/mL in the F_IO₂ 0.3 and 0.8 groups, respectively (p = 0.132). Acute kidney recovery, defined as an increase in the estimated glomerular filtration rate ≥ 25% of baseline in 48 h, was more common in the F_IO₂ 0.3 group (65% vs. 39%, p = 0.042). Other clinical outcomes were comparable between the groups. Conclusions The F_IO₂ level did not have a significant effect on periprocedural myocardial injury following TAVI. However, considering the marginal results, a benefit of low F_IO₂ during TAVI could not be ruled out.