Objective To identify risk factors of perceived stress among proton radiotherapy patients based on association rules mining method, providing insights for targeted intervention strategies.Methods A convenience sample of 335 patients undergoing proton radiotherapy from September 2024 to April 2025 was recruited. Data were collected using a general information questionnaire, the Perceived Stress Scale (PSS), the Chinese version of the Family Resilience Scale, and the Social Support Rating Scale (SSRS). A combination of Lasso regression and the Apriori algorithm was used to analyze the data. The validity of the association rules was verified using the χ2 test. A panel of 10 experts identified and selected clinically valuable rules through a two-round, in-person consensus meeting. Results A high level of perceived stress was reported by 76.72% of patients. Lasso regression identified eight significant influencing factors: number of children, monthly family income, commercial insurance status, receipt of concurrent chemotherapy, disease recurrence or metastasis, history of radical surgery, family resilience, and social support. From an initial 2,022 rules generated by the Apriori algorithm, 13 clinically valuable association rules were selected following expert review and χ2 testing. Conclusion Perceived stress in patients undergoing proton radiotherapy is influenced by a combination of demographic, clinical, social, and familial factors. Healthcare professionals should develop more scientific and effective intervention strategies tailored to individual patient characteristics and associative patterns, with the aim of alleviating patients′ perceived stress and facilitating disease recovery.