(1) Background: To evaluate the effects of an AI-based denoising post-processing software solution in low-dose whole-body computer tomography (WBCT) stagings; (2) Methods: From 1 January 2019 to 1 January 2021, we retrospectively included biometrically matching melanoma patients with clinically indicated WBCT staging from two scanners. The scans were reconstructed using weighted filtered back-projection (wFBP) and Advanced Modeled Iterative Reconstruction strength 2 (ADMIRE 2) at 100% and simulated 50%, 40%, and 30% radiation doses. Each dataset was post-processed using a novel denoising software solution. Five blinded radiologists independently scored subjective image quality twice with 6 weeks between readings. Inter-rater agreement and intra-rater reliability were determined with an intraclass correlation coefficient (ICC). An adequately corrected mixed-effects analysis was used to compare objective and subjective image quality. Multiple linear regression measured the contribution of “Radiation Dose”, “Scanner”, “Mode”, “Rater”, and “Timepoint” to image quality. Consistent regions of interest (ROI) measured noise for objective image quality; (3) Results: With good–excellent inter-rater agreement and intra-rater reliability (Timepoint 1: ICC ≥ 0.82, 95% CI 0.74–0.88; Timepoint 2: ICC ≥ 0.86, 95% CI 0.80–0.91; Timepoint 1 vs. 2: ICC ≥ 0.84, 95% CI 0.78–0.90; all p ≤ 0.001), subjective image quality deteriorated significantly below 100% for wFBP and ADMIRE 2 but remained good–excellent for the post-processed images, regardless of input (p ≤ 0.002). In regression analysis, significant increases in subjective image quality were only observed for higher radiation doses (≥0.78, 95%CI 0.63–0.93; p < 0.001), as well as for the post-processed images (≥2.88, 95%CI 2.72–3.03, p < 0.001). All post-processed images had significantly lower image noise than their standard counterparts (p < 0.001), with no differences between the post-processed images themselves. (4) Conclusions: The investigated AI post-processing software solution produces diagnostic images as low as 30% of the initial radiation dose (3.13 ± 0.75 mSv), regardless of scanner type or reconstruction method. Therefore, it might help limit patient radiation exposure, especially in the setting of repeated whole-body staging examinations.