Producer Responsibility Organizations (PROs) are professional organizations that take responsibility for collecting and treating E-waste in an eco-friendly way on behalf of producers. However, they face several challenges in effective e-waste management (EWM). The current study aims to identify and model key challenges in EWM from PROs’ perspective in the Indian context. We identified key challenges to EWM through a literature review and discussions with experts. The expert team validated and mapped key challenges into the EWM process, from collection to disposal. We employed the DEMATEL method to model key challenges. Nine key challenges were identified. Findings suggest that a knowledge-sharing platform is a crucial step in EWM as it allows PROs to share best practices. In addition, collaboration among stakeholders, usage of tracking systems, and eco-design could play a key role in sustainable and effective EWM. This study provides various mitigation strategies to overcome key challenges in the adoption of sustainable EWM. Furthermore, PROs can use the proposed conceptual framework to identify challenges that may be faced during different EWM process stages.