AK104 is a novel antibody targeting programmed cell death protein 1 (PD-1)/cytotoxic T-lymphocyte-associated protein 4. This study aimed to evaluate the safety, tolerability, and efficacy of AK104 in treating patients with advanced solid tumors who failed prior programmed cell death protein 1/programmed death-ligand 1 (PD/PD-L1) therapies. Clinical data from 135 patients with advanced solid tumors who failed PD/PD-L1 therapies were retrospectively analyzed. Patients received AK104 at a dose of 6 mg/kg every 2 weeks. Baseline demographic characteristics, clinical outcomes, adverse reactions, overall survival, progression-free survival, and quality of life assessments were analyzed. Following AK104 treatment, 17.78% of patients achieved a partial response, while 80.74% experienced stable disease, resulting in a disease control rate of 98.52%. The 1- and 2-year overall survival rates were 48.15% and 31.11%, while progression-free survival rates at 6 months and 1 year were 53.33% and 28.15%, respectively. Post-treatment, significant improvements in the quality-of-life scores, as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and EuroQol 5 Dimensions Visual Analog Scale, were observed post-treatment. Immune-related adverse events were common, affecting 85.19% of patients, with diarrhea, enteritis, pneumonia, and thyroid dysfunction being the most frequently reported. AK104 demonstrated the ability to induce clinical responses, extend survival, and enhance quality of life in patients with advanced solid tumors who had previously failed PD-1/PD-L1 therapies, underscoring its potential as a promising therapeutic option. However, the high incidence of immune-related adverse events necessitates vigilant monitoring and management to maximize its clinical utility. Further prospective studies are warranted to validate and extend these findings in broader patient populations.