The Cross River Rainforest of South Eastern Nigeria is one of Africa’s last remaining areas of pristine tropical high forest, extremely rich in a wide variety of flora and fauna species, and is among the twenty five biodiversity hotspots in the world. The forest has important biophysical properties which affect local, regional and global environmental quality. Using a combination of document research, GIS report, field observations, interviews and focus group discussions, the study reveals that the ecological integrity of this forest is being seriously threatened by a myriad of human activities, such as unsustainable agricultural practices, illegal logging, population explosion/expansion of human settlements, construction of highways, mining activities, and high unemployment/pressure on natural resources. All the above factors have combined to impact heavily on the depletion and extinction of valuable flora and fauna species in the region. Rigorous research-based innovative forestry and biodiversity policies and programmes, forest restoration initiatives, community-based forest management, and sustainable land use practices are recommended to save the Cross River Rainforest from total destruction.