Kayes Region (Bambara: ߞߊߦߌ ߘߌߣߋߖߊ tr. Kayi Dineja, Arabic: منطقة كايس, romanized: minṭaqa Kāyas) is one of ten first level national subdivisions in Mali called Regions. It is the first administrative area of Mali and covers an area of 120,760 square kilometres or 46,630 square miles. Its capital is the town of Kayes. The province was historically part of the Ghana Empire and the Mali Empire.

The region of Kayes is bordered to the north by Mauritania, to the west by Senegal, to the south by Guinea and to the east by the region of Koulikoro.

In 2009 the region has a population of 1,996,812 inhabitants. Ethnic groups of the area include Soninkés, Khassonkés, Malinkés, Dialonkés, and Fulas (French: Peuls; Fula: Fulɓe).

Several rivers cross the region: the Baoulé, the Bafing, and the Bakoy which join at the town of Bafoulabé to form the Sénégal River. The Falls of Félou (15 km from Kayes), the Falls of Gouina (60 km to the south-east of Kayes on the Sénégal River), Talari Gorges, Lake Magui and Lake Doro are located in the region.

At the Guinean border, the climate is rather wet, but becomes Sudanian and later Sahelian to the north.

The largest cities in the region are Kayes, Kita, Bafoulabé, Nioro du Sahel, Diéma, Yélimané, Diangounté, Sadiola, and Kéniéba The Bafing National Park and the Boucle du Baoulé National Park are located in the region.

For administrative purposes the Region of Kayes is divided into seven cercles:

The region of Kayes is the cradle of the Kingdom of Khasso founded at the beginning of the 19th century.