Objectives: Polysubstance abuse can result in significant adverse effects on an individual’s physical, mental, and social health, affecting families and leading to increased stress, anxiety, depression, and financial difficulties. This study evaluated the effect of a psychoeducational program to enhance expressed emotion (EE) and reduce the burden of care among family caregivers of patients with polysubstance abuse. Methods: The study was conducted at the addiction clinic in the El Abasia Psychiatric and Mental Health Hospital, in Egypt using a quasi-experimental design that involved a pre-test and a post-test. The study involved 62 caregivers of polysubstance abuse patients, and data were collected in the period from June to December 2022. The data were collected by online survey which includes socio-demographic data assessment questionnaire, caregivers’ knowledge about polysubstance abuse form, patterns of EE scale, and Zarit Burden Interview scale. Results: The ages of 72.60% of family caregivers ranged from 30 to 40 years. The total knowledge score was 54.6% pre-program implementation versus 87.2% post-program. Furthermore, 70.7% of caregivers had high EE pre-program versus 26.4% post-program. In addition, 78.4% of caregivers reported high burden pre-program implementation versus 32.8% post-program. The scores related to caregivers’ EEs and burden following the implementation of a psycho-educational program were significantly improved, (p<0.001). The total EE and total burden scores of caregivers were more significantly positively correlated pre-program than post-program implementation (p<0.001). Conclusion: Implementing the psycho-educational intervention had resulted in a positive statistically significant impact on improving the EE of family caregivers and decreasing the burden of patient care.