Mkhambathi Nature Reserve is a protected area at Lusikisiki in the Eastern Cape, South Africa. It is 7,720 hectares, with the Pondoland Marine Protected Area off its coastal edge. The reserve is located in the Pondoland Centre of Plant Endemism and the greater Maputaland–Pondoland–Albany Hotspot, and is covered in open grassland, dotted with patches of indigenous forest, swamp forests and flanked by the forested ravines of the Msikaba and Mtentu rivers. The Reserve was listed as a protected Ramsar site in 2025.