Arsenic poisoning has become one of the major environmental concerns in the world as millions of people have been exposed to excessive arsenic through contaminated drinking water. In this study, ICR mice were introduced to 0.8 -4.8 mgL-1 arsenic, synonymous to arsenic detected from streams and soils in Buruli Ulcer endemic communities of the Amansie West District of the Ashanti Region of Ghana, via their drinking water. Mice with arsenic exposure of 4.0-4.8 mgL-1 developed inflammation, erythema and open ulcers on skin (with scab formation). The scabs upon examination were negative for acid fast bacilli. Histopathological studies revealed liver and spleen damage. There was hepatic cell swelling with the loosening of cell wall and degenerative change with cells showing cytoplasmic vacoulation with nuclear blebbing and gradual cell loss. The spleen developed a lymphoid background with multinucleate cells formation. Hematological examination revealed significant dose-dependent decrements in white blood cells indicating a detrimental effect on the body’s immune system, a situation which makes the body susceptible to infections including M. ulcerans. The mean corpuscular volume of red blood cells also decreased significantly indicating microcytosis. High levels of arsenic in tissue (possibly from accumulation) cause inflammation, erythema and open ulcers on the skin, and has the potential to cause liver and spleen damage, reduced immune system function, and red blood cell microcytosis in ICR mice.