Due to continuous focus on sustainability and circular economy, product take-back programs are becoming increasingly relevant and attractive. Thus, closed-loop manufacturing systems have to be designed and developed for disassembly, reprocessing of materials, re-assembly, and remanufacturing in a cost-efficient way. Compared to traditional manufacturing, this involves a higher need for changeability due to higher uncertainty, e.g. in terms of timing and quantity that the system needs to handle, uncertainty in quality and materials of received items, and in particular significant variety in returned items, the system should be designed to process. Therefore, the objective of this paper is to investigate how reconfigurability, as the enabler of changeability at manufacturing system level, can be utilised to aid challenges in closed-loop manufacturing systems for product take-back. Initially, insights from an industrial case are presented regarding challenges in establishing and operating closed-loop manufacturing systems for product take-back programs. Secondly, different closed-loop manufacturing concepts applying the principles of reconfigurability are proposed and evaluated in terms of cost and robustness towards the inherent uncertainties in supplied end-of-use items. The results show significant potential of utilising a modular and platform-based approach towards meeting supply uncertainties through reconfiguration, which allows for a more efficient setup for product take-back.