Heat transfer deterioration (HTD) problems can undermine the thermal safety of heating tubes for supercritical carbon dioxide (S-CO2) flows. Relevant experimental evidence is highly desired, but most cases were investigated for small tube diameters (below 10 mm) and under limited operation parameters, far from the industry-scale applications. In the present work, large tubes (24 mm) are investigated experimentally with pressures of 7.5–15 MPa, mass flow rates of 100–1200 kg·m−2·s−1 and heat fluxes of 30–350 kW·m−2. The seriousness of HTD in large tubes was experimentally confirmed, and the mechanism is explored via a carefully-designed comprehensive comparison between present numerical simulations and experimental tests. Detailed analysis of vapor-like film development inspires us to mitigate the problem using structured-inner-surface, from the viewpoint of “supercritical pseudo-boiling”. This inspiration is further evaluated numerically: five types of enhancement structures are proposed to interfere with the development of vapor-like film. It was found that the proposed methods can fully prevent HTD problems, and especially the conical strips can achieve a high heat transfer performance (with performance evaluation criteria PEC of 1.21–1.35) and are thus recommended for HTD prevention in vertical large-diameter tubes under near-critical conditions. Overall, the experimental tests and numerical explorations can deliver more evidence on the theory and applications of supercritical fluid flow and heat transfer.