This study investigated sediment spatial and seasonal distribution of trace elements (TEs) (n = 16) and human health effects along the Hooghly River Estuary (India). The index of geo-accumulation (Igeo), enrichment factor (EF), hazard quotient (HQ), modified hazard quotient (mHQ) and toxic risk unit (TRI) were calculated to estimate sediment pollution level, while hazard index (HI) and lifetime cancer risk (LCR) were used to assess TEs enrichment vs. human health. The concentrations (µg/g dry weight) of TEs were: Cd (0.01–1.58), Cr (41.98–105.49), Cu (16.41–51.09), Ni (28.37–63.90), Fe (22075–47919), Mn (423–630), Co (11.43–23.11), Zn (48.82–105.81), V (63.92–138.92), Pb (25.01–43.27) and Ti (0.18–3.50); As (2.92–16.26), B (59.34–98.78), Si (11.52–98.78); Be (1.71–4.81), Ba (95.23–293.72). From Igeo and EF, Cd was the major contaminant, while Ni presented moderate/high contamination (HQ and TRI). Children were more exposed to carcinogenic and non-carcinogenic risks compared to adults. For non-carcinogenic substances, no significant risk was found to both children and adults (HIs < 1). The LCR for Cr (3.924 × 10−4 for children) and As (1.379 × 10−4 for children) was higher than the threshold limit value (TLV, 10−4 and 10−6) indicating significant carcinogenic risks to be managed.