Anaerobic digestion (AD) of organic waste (OW) for methane production is generally inefficient. Supplementation of AD systems with traditional materials (e.g., electroconductive materials) is a current focus of research and has been reported to assist methanogenesis by enhancing the productivity of microbial metabolism among syntrophic anaerobes. Unlike in the AD of organic wastewater, in which microbial cells come into direct contact with the dissolved substrate, in the complex multi-phase AD system of OW, low substrate bioavailability is an inevitable obstacle to microbial syntrophism for methanogenesis. Accordingly, we propose that improving substrate bioavailability and microbial syntrophism is a powerful strategy for ensuring material-assisted efficient AD of OW. Based on the above considerations, metal–organic frameworks (MOFs), with their exceptionally high porosity, outstanding multi-functionality, and tuneable structures, have excellent potential for application in multi-phase anaerobic systems of OW to integrate substrate bioavailability and microbial syntrophism and drive efficient AD. In addition, MOFs with designable and tuneable natures have great potential for use in identifying suitable materials for anaerobic systems for different types of OW via machine-learning technologies, thereby effectively enhancing methanogenesis from OW. However, the sustainable application of MOFs in AD and the corresponding environmental risks warrant further investigation.