Objective To explore the mediating effect of disease acceptance between psychological resilience and psychological distress in patients newly diagnosed with HIV/AIDS, and to provide evidence for targeted psychological interventions. Methods From May 2019 to April 2024, 285 newly diagnosed HIV/AIDS patients were recruited via convenience sampling.Participants completed the General Information Questionnaire, the Connor-Davidson Resilience Scale, the Acceptance of Illness Scale, and the Distress Thermometer. Results The mean scores were:psychological resilience 62.47±7.15, disease acceptance 25.57±4.98, and psychological distress 6.76±1.68.Psychological resilience was positively correlated with disease acceptance and negatively correlated with psychological distress; disease acceptance was negatively correlated with psychological distress (all P＜0.05).Disease acceptance partially mediated the relationship between psychological resilience and psychological distress, with the mediating effect accounting for 54.00% of the total effect. Conclusion Newly diagnosed HIV/AIDS patients experience significant psychological distress.Disease acceptance mediates the effect of psychological resilience on psychological distress.Clinical staff should implement acceptance-based psychological interventions to enhance patients′ resilience, improve disease acceptance, and alleviate distress.