Background <p>Previous studies suggest that HDLs may protect against the effects of acute injury. Given their multiple beneficial properties, this study aimed to investigate whether exogenous HDLs administration reduces acute tissue damage in a HgCl₂-induced renal injury model, potentially contributing to health improvement and disease prevention.</p> Methods <p>Acute tubular injury was induced in male Wistar rats with a single intraperitoneal dose of 3.5&#xa0;mg/kg HgCl₂ (ATI group). Two additional groups received either HDLs (ATI + HDL group) or apolipoprotein B-containing lipoproteins (ATI + Lp-B) isolated from human plasma, at a dose equivalent to 0.9&#xa0;mg of cholesterol per 100&#xa0;g of body weight, administered twice on consecutive days. The study follow-up lasted four days. Urine and blood samples were collected to evaluate renal function markers. Histological analysis was also performed. In vitro, the ability of these lipoproteins to maintain cell viability under mercury exposure was assessed using the HEK-293 cell line.</p> Results <p>During the follow-up, plasma creatinine decreased, creatinine clearance improved, and proteinuria levels recovered more rapidly in the ATI + HDL group than in the ATI group. Glucosuria remained similar across both groups throughout the study. Histological analysis revealed increased cellularity and reduced necrosis in the kidneys of the ATI + HDL group compared to ATI rats. Rats in the ATI + Lp-B group died 48&#xa0;h after HgCl₂ administration and tubular lesions were more severe. In vitro, HDLs effectively preserved cell viability under mercury exposure, while Lp-B did not provide similar protection.</p> Conclusion <p>Exogenous HDLs supplementation improves biochemical markers of renal function in vivo and promotes cell survival&#xa0;in vitro in a HgCl₂ toxicity model. These findings reveal a new beneficial property of HDLs, unlike apo B-containing lipoproteins, and underline the importance of such interventions for health support and disease management.</p>