Increase in riverine nutrient loads was generally recognized as the primary cause of coastal deoxygenation, whereas the role of other riverine factors, especially suspended sediments, has received less attention. This study aims to discern the impacts of anthropogenic alterations in various riverine inputs on the subsurface deoxygenation over the past three decades in a large river-dominated estuary, the Pearl River Estuary (PRE). Using a physical-biogeochemical model, we reproduced the observed dissolved oxygen (DO) conditions off the PRE in the historical period (the 1990s with high suspended sediments concentration (SSC), high DO, and low nutrients) and the present period (the 2010s with low SSC, low DO, and high nutrients). In the 2010s, the PRE exhibited more extensive and persistent summer hypoxia, with the low oxygen area (DO < 4 mg/L) expanding by ~148% (to ~2926 km²) and the hypoxia area (DO < 3 mg/L) increasing by 192% (to ~617 km²). Low-oxygen durations extended to 15-35 days, and three distinct hypoxic centers formed under different controlling factors. Single-factor experiments suggested that decreased riverine DO content (46%) alone expanded low-oxygen areas in the upper estuarine regions by 44%, the decreased SSC (by 60%) alone cause a 47% expansion in the lower reach of PRE, and the increased nutrients alone (100% in dissolved inorganic nitrogen and 225% in phosphate) drove a 31% expansion. In comparison, the combined nutrient increases and the SSC declines synergistically enhanced primary production and bottom oxygen consumptions (dominated by sediment oxygen uptake), amplifying low-oxygen (104%) and hypoxic (192%) area growth in lower estuaries. Our results revealed that SSC declines, by improving light availability for productivity, play a larger role than nutrient increases in exacerbating deoxygenation off the PRE. This synergy complicates hypoxia mitigation efforts focused solely on nutrient controls. Given the widespread global declines in riverine suspended sediments, our findings underscore the importance for incorporating sediment-mediated processes, a relatively overlooked factor, in coastal deoxygenation studies.