Objective To investigate polypharmacy burden in patients with chronic comorbidities and analyze the influencing factors, and to provide references for healthcare professionals in developing targeted medication management plans.Methods A convenience sampling method was used to select 277 patients with chronic comorbidities admitted from October 2023 to July 2024 as study participants.Data was collected using a general information questionnaire, the Medication Literacy Assessment Scale, the Beliefs about Medicines Questionnaire-Specific, the Medication Adherence Questionnaire, and the Living with Medicines Questionnaire.Both univariate and multivariate analyses were used to assess the polypharmacy burden and its influencing factors.Results The polypharmacy burden score in chronic comorbid patients was (113.70±14.04) points.Significant influencing factors included residence, education level, number of medications, medication-related concerns, medication literacy, and medication adherence (all P＜0.05).Conclusion Patients with chronic comorbidities bear a moderate polypharmacy burden.It is recommended that healthcare professionals conduct personalized interventions based on patient characteristics to improve medication self-management abilities and reduce medication burden.