Researchers worldwide are increasingly concerned about the loss of longitudinal river connectivity. Here, we determined how the construction of serial weirs influences the nutrient regime, organic matter, solids deposition, water flow, and general water chemistry in a natural river during 2017–2021. The results indicated that the monsoon rainfall intensity primarily governed the seasonal water-quality trends. Downriver weirs were more affected than upriver weirs, highlighting the significance of water residence time (WRT). The total phosphorus (TP) showed a strong positive relationship with inflow (R2 = 0.847), outflow (R2 = 0.845), and WRT (R2 = 0.734). However, total suspended solids (TSS) had a lesser effect than TP, i.e., inflow (R2 = 0.62), outflow (R2 = 0.61), and WRT (R2 = 0.541). The sestonic Chl-α showed significant spatial variation year-round, e.g., Chl-α was < 25 µg·L−1 in up- and midriver weirs and > 25 µg·L−1 in downriver weirs pre-monsoon. A monsoon dilution effect on Chl-α was observed during intensive rainfall, further augmenting the weir impact. The principal component analysis yielded a 76.016% cumulative variance. The chemical health status was ‘fair’ in the upriver and ‘poor’ in the downriver gradients. In conclusion, sestonic Chl-a, WRT, chemical health, and inflow along the river gradient were interlinked, indicating an evident effect of weir installation on river water quality. The weirs significantly harmed the river’s lotic properties, causing it to morph into a lotic-lentic environment. Water-quality degradation was reflected in three river zones (up-, mid-, and downriver), indicative of the impact of weir installation.