Ecological systems can undergo large changes and regime shifts that are either catastrophic, neutral, or desirable. Rivers worldwide have recently undergone desirable regime shifts related to re-oligotrophy, which is a notable and ongoing reduction in concentrations of total suspended solids (TSS), total N, total P, or phytoplankton. For example, the Upper Mississippi River, USA, has experienced major water-quality changes in multiple river reaches in recent decades. In this study, we sought to understand the timing and magnitude of re-oligotrophy in the Mississippi River over a 20-y period. We used 2 topological data analysis algorithms to address hypotheses related to the following questions: What were the order and timing of water-quality changes? What was the time period over which the major changes occurred? What was the magnitude of water-quality change before and after change points (i.e., specific years when water-quality conditions transitioned abruptly to new states)? We examined 6 water-quality state variables that defined the ecological regime for the Upper Mississippi River. In one river reach, we found that strong reductions in phytoplankton/chlorophyll a had occurred first (2008), followed by total P (2013), and last in TSS (2014). In a downriver reach, we found notable reductions for chlorophyll a (2007) but substantial increases in TSS (2013). In both reaches, the water-quality changes trended over ≥15 y, but the largest changes and a likely regime shift occurred in just 6 y. The timing (2007–2014) and range (~6 y) of water-quality changes were similar between the 2 river reaches, but the directionality of the regime shift indicated re-oligotrophy for the upstream reach and water-quality degradation for the downstream reach. Topological methods applied to long-term datasets can aid our understanding of re-oligotrophication and degradation processes and may help resource managers restore desirable regimes.