The ecological impact of human settlement on the water quality of Lower Cross River, Nigeria was evaluated. The physical and chemical conditions of the river water were determined from January to August, 2011. Three stations comprising Itu in Akwa Ibom State with intense human activities (station 2), its upstream (without human settlement) at Cross River State (station 1) and the downstream (station 3) were sampled. The Parametric One Way Analysis of Variance (ANOVA) indicated that of the 17 physical and chemical parameters determined, only water level and COD were found to be significantly different ( < 0.01) among stations. The spatial variations in the level of significant correlation of the physical and chemical parameters among the stations and the higher level of interrelationship in downstream station 2 and 3 than station 1 could be attributed to inputs resulting from human settlement. Comparison between some parameters with Standard Organization of Nigeria, and World Health Organization maximum permitted levels for drinking water indicated that the water was not polluted. However, the BOD and COD concentrations of greater than 2 mg/L and 20 mg/L respectively were indicative of pollution.