Soils must receive maximum protection to assure sustainable agriculture and quality food production. Heavy metals tend to accumulate in the soil rather than decompose and at a certain limit of their content, toxic consequences for living organisms occur.  This research was conducted to survey the contamination status of Cd, Cr, Ni, and Pb and microbial activity in soils affected by long-term sugarcane monoculture in Upper Egypt. The rise of diacetate fluorescein hydrolysis (FDA) ranged from 86.25 to 201.25 mg kg^-1 soil·h^-1 in sugarcane monoculture fields, while the increase under crop rotation fields showed higher and significant values ranged from 207.25 to 266.67 mg kg^-1 soil·h^-1. In this study, generally soil microbial biomass and enzymatic activity was usually and significantly higher under crop rotation than sugarcane monoculture.  The highest potential ecological risks were found in soils under long-term irrigated sugarcane monoculture, while being moderate for crop rotation. Under both sugarcane monoculture and crop rotation farming systems, cadmium Cd was observed to be the urgency pollutant with the highest degree of contamination even though Cd had the lowest average concentration (Cd 27.03 mg kg^-1) in sugarcane monoculture fields, and Cd (10.46 mg kg^-1) in crop rotation. In view of the impacts of these potentially toxic elements of cadmium (Cd), chromium (Cr), nickel (Ni) and lead (Pb), on the ecological system and public health, the introduction of new management practices in sugarcane monoculture fields are essential to protect the environment and to achieve future sustainability in sugarcane production in Upper Egypt.