Background <p>Frailty is a multidimensional state related to multidomain risk factors, including demographic, physical, and psychological variables. The risk factors affecting frailty in postoperative older patients and the interactions between these factors remain unclear. Network analysis provides a novel method for conceptualizing interconnections among complex multidimensional data.</p> Objective <p>This study aimed to explore the relationships between demographic, physical, psychological, surgery-related factors and frailty in postoperative older adults.</p> Methods <p>The Early-Warning model of Perioperative Adverse Events for older adults (EPAE) is an prospective, multicenter, observational study. Participants were assessed for demographic variables, clinical and physical variables, psychological and cognitive variables, surgery-related variables, and frailty assessment during the period of hospitalization. A perioperative network was constructed to identify key risk factors associated with postoperative frailty and specific paths within the network.</p> Results <p>2678 older adults were enrolled in the study. Postoperative frailty in older adults was strongly associated with postoperative activities of daily living (ADL) (average edge Weight=-0.26), Morse Fall Scale (MFS)(average edge Weight = 0.19), Hemoglobin(Hb) (average edge Weight=-0.16), Patient Health Questionnaire-9(PHQ-9)(average edge Weight = 0.14), and Mini-Cog(average edge Weight=-0.1). PHQ-9 played mediating roles between Feeling nauseated, Emesis, physical Exam, and Duration of symptoms score (I-FEED) and frailty, Athens Insomnia Scale(AIS) and frailty. Postoperative frailty, Social supporting rating scale(SSRS), PHQ-9, and Mini-Cog were the strongest bridge symptoms in the network.</p> Conclusions <p>Postoperative frailty was the most prominent bridge symptom in the perioperative network, which was strongly associated with postoperative physical(ADL, Hb, MFS) and psychological factors(PHQ-9 and Mini-Cog). Depression may mediate the associations between postoperative clinical symptoms(gastrointestinal dysfunction and insomnia) and postoperative frailty. Our findings support a clarion call for dynamic assessments for postoperative frailty, and intervention programs targeting specific frailty-related factors, especially depression, to prevent or reverse frailty for older adults after surgery.</p> Trial registration <p>This study was registered in the Chinese Clinical Registry Center (registration no. ChiCTR2300071535). Date: 17-5-2023.</p>