The process of macroplastic (>0.5 cm) fragmentation results in the production of smaller plastic particles (micro- and nanoplastics), which threaten biota and human health and are difficult to remove from the environment. The global coverage and long retention times of macroplastic waste in fluvial systems (ranging from years to centuries) create long-lasting and widespread potential for its fragmentation and the production of secondary micro- and nanoplastics. However, the pathways and rates of this process are unknown, which constitutes a fundamental knowledge gap in our understanding of macroplastic fate in rivers and the transfer of produced microparticles throughout the environment. To set the stage for future research aiming to fill this gap, we present a conceptual framework which identifies two types of riverine macroplastic fragmentation controls: intrinsic (resulting from plastic item properties) and extrinsic (resulting from river characteristics and climate) processes. First, based on the existing literature, we identify the intrinsic properties of macroplastic items that make them particularly prone to fragmentation (e.g., the film shape, low polymer resistance, previous weathering). Second, we propose a conceptual model showing how extrinsic controls can modulate the intensity of macroplastic fragmentation in perennial and intermittent rivers. Using this model, we hypothesize that the inundated parts of perennial river channels—as specific zones exposed to the constant transfer of water and sediments—provide particular conditions that accelerate the physical fragmentation of macroplastics resulting from their mechanical interactions with water, sediments, and riverbeds. The non-inundated parts of perennial river channels provide conditions for biochemical fragmentation via photo-oxidation. In intermittent rivers, the whole channel zone is hypothesized to favor both the physical and biochemical fragmentation of riverine macroplastics, with the dominance of the mechanical type during the wet season. Our conceptualization aims to support future experimental works quantifying macroplastic fragmentation rates in different types of rivers.