Water quality of Lake Burullus was investigated through evaluating their impact on health and genetic alterations of native Lake Burullus Biomphalaria alexandrina snails and Oreochromis niloticus fish samples and non-native ones exposed in simulating experiments for six weeks to lake-water/sediment from three lake sites; El-Hamoul, Mottobus and Sidi-Salem. El-Hamoul and Sidi-Salem sites showed high levels of total dissolved solids and conductivity, while recorded high levels of Zn and Cd in their simulating experiments. Native snails' tissues showed higher Cu bioaccumulation, while non-native showed higher levels of Zn and Cd bioaccumulation. Most non-native exposed fish in the three simulating experiments showed higher bioaccumulation in all organs than native fish from Lake Burullus. Snail hemolymph showed significant increase in small granulocytes and decrease in hyalinocytes, while fish blood showed highly significant increase in WBCs of native fish collected from El-Hamoul and Sidi-Salem sites and non-significant decrease in Hb and RBCs in all samples. Genetic alterations were investigated by ISSR-PCR technique demonstrated 33 amplified bands of which 30 % were polymorphic among snail samples, while generated 26 amplified bands among fish samples of which 40% were polymorphic. Cluster analysis using dendrograms based on genetic similarity matrices was constructed between each of  snail and fish samples showed different degrees of similarities and divergent as showed it cluster between samples of control, lake and non-native Mottobus indicating lower pollution;while non-native El-Hamoul sample was the most divergent followed by non-native Sidi-Salem sample indicating higher pollution level. So, heavy metals bioaccumulation, hematological, and molecular analysis indicate that water quality of Lake Burullus has negative effects on snail and fish samples graded from Sidi-Salem > El-Hamoul >Mottobus samples.