Secretion of mucus by epidermal goblet cells protects fish against many biological, physical, and chemical insults encountered in the environment. This study monitored changes in hemoglobin concentration in epidermal mucus and in the density, diameter, and mucus quality of epidermal goblet cells in the mummichog, Fundulus heteroclitus, following exposure to creosote‐contaminated sediment from the Elizabeth River, Virginia, USA. Fish were exposed for 13 d in flow‐through aquaria to either uncontaminated (US) or contaminated (CS) sediments and were sampled periodically. The condition index was lower and the mortality rate and the occurrence of epidermal lesions were higher in CS‐exposed fish than in US‐exposed fish. Hemoglobin contents in epidermal mucus from the former group were significantly higher than from the latter. Significant reductions in both size and density of goblet cells in CS‐exposed fish suggested a mucus secretion rate exceeding its production rate. Significant changes in mucin types between treatments did not occur until day 13 and are not believed to be directly related to the creosote present in the contaminated sediment. These results all indicate that exposure to creosote‐contaminated sediment had a profound and deleterious effect on fish health.