The Egyptian coast of Gulf of Aqaba, north of the Red Sea, suffers from severe destruction and deterioration in habitat and biodiversity due to anthropogenic activities and flooding. The present work aims to evaluate the impacts of different human activities and flooding on the biodiversity of macrobenthic invertebrates along the Egyptian coast of the Gulf of Aqaba. From January 2019 to December 2019, many field trips (12 trips) were conducted to survey macrobenthic invertebrate communities and monitor water quality at nine sites within three sectors along the study area. Each site was divided into four ecological zones and one of five categories, according to the main activities at each site. Furthermore, satellite data were used to monitor the progress of land use and turbidity in the study area. Therefore, the current study assesses the relationship between these factors and water quality and macrobenthic invertebrate distributions, similarity, diversity, dominance and abundance. The results revealed that 53 macrobenthic invertebrate species belonging to three phyla (Mollusca, Echinodermata and Annelida) and one subphylum (Crustacea) were recorded. The echinoderm Echinometra mathaei was the major eudominant species. The northern part of the Gulf was higher in abundance and diversity with low land use and lowest water turbidity, while the south part showed contrary findings. All statistical analysis confirmed that the dissolved oxygen concentration was considered the only limiting factor for the abundance and diversity of macrobenthic invertebrates. Also, the variation in activities at investigated sites affected the dominance state of species in each site. Moreover, GPS data confirmed that the tourism activity had the largest influence on marine ecosystems and biodiversity, followed by fishing and desalination practices. Otherwise, flooding has significant influence on marine habitats and creates a habitat in which other certain species can survive. In the absence of awareness, intervention and disregard for the effective coastal zone management concept, especially for the unique marine ecosystems such as the Gulf of Aqaba, the degradation of biodiversity will continue until extinction, and human life is rendered unsustainable.