The COVID-19 pandemic and sudden lockdown have severely hampered the country’s economic growth and socio-cultural activities while imparting a positive effect on the overall fitness of the environment especially air and water resources. Increased urbanization and rapid industrialization have led to rising pollution and deterioration of rivers and associated sectors such as agriculture, domestic and commercial needs. However, various available studies in different parts of the country indicate that the COVID-19 pandemic has changed the entire ecosystem. But it is noted that studies are lacking in the southern Western Ghats region of India. Therefore, the present study attempts to investigate how the continuous lockdowns affect the River Water Quality (RWQ) during lockdown (October 2020) and post-lockdown (January 2021) periods in the lower catchments (Eloor-Edayar industrialized belt) of Periyar river, Kerala state, South India. A total of thirty samples (15 samples each) were analyzed based on drinking water quality, irrigational suitability, and multivariate statistical methods to evaluate the physical and chemical status of RWQ. The results of the Water Quality Index (WQI) for assessing the drinking water suitability showed a total of 93% of samples in the excellent and good category during the lockdown, while only 47% of samples were found fit for drinking during the post-lockdown period. Irrigational suitability indices like Mg hazard, KR, PI, SAR, and Wilcox diagram revealed lockdown period samples as more suitable for irrigational activities compared to post-lockdown samples with site-specific changes. Spearman rank correlation analysis indicated EC and TDS with a strong positive correlation to Ca
2+
, Mg
2+
, Na
+
, K
+
, TH, SO
4
2−
, and Cl
−
during both periods as well as strong positive correlations within the alkaline earth elements (Ca
2+
and Mg
2+
) and alkalis (Na
+
and K
+
). Three significant components were extracted from principal component analysis (PCA), explaining 88.89% and 96.03% of the total variance for lockdown and post-lockdown periods, respectively. Variables like DO, BOD, Ca
2+
, NO
3
−
, and Cl
−
remained in the same component loading during both periods elucidating their natural origin in the basin. The results of health risk assessment based on US EPA represented hazard quotient and hazard index values below the acceptable limit signifying no potential noncarcinogenic risk via oral exposure except As, suggesting children as more vulnerable to the negative effects than adults. Furthermore, this study also shows rejuvenation of river health during lockdown offers ample scope to policymakers, administrators and environmentalists for deriving appropriate plans...