Macron paid a brief visit to the Horn of Africa state for talks with its President Ismail Omar Guelleh and to see French troops ahead of the end-of-year holidays.
A number of African countries have recently ended military accords with France and ordered out its troops.
Macron said during talks with Guelleh that the French presence in Djibouti was key for the security of the Indo-Pacific trade routes between Europe and Asia.
"This presence in Djibouti is of course also oriented towards the Indian Ocean, the Indo-Pacific," Macron said.
He added that France's Indo-Pacific strategy "could not work without the French forces in Djibouti".
Macron told French troops on Friday that the base could take on a greater importance as it could be "reinvented" to become a launch point for missions in Africa.
"In several countries, we had historic established bases. We have wanted to rethink that model," he said in the latest comments.
But he insisted that Djibouti was not part of these plans "as for decades the nature of our base here, our operations, is profoundly different".
Djibouti looks out onto a vast zone in the Indian Ocean -- a region that includes India and China as well as sea routes that account for a huge proportion of world trade.
French troops left Mali, Burkina Faso and Niger in 2022 and 2023 after the military juntas that took power in those countries broke defence accords with the former colonial power.
It has started withdrawing jets and troops from Chad in recent weeks after the country's military leader cut military ties. Senegal made a similar request in November.
The Djibouti president highlighted his small country's "privileged relations" with France. A defence accord was renewed in July.
Accords for the building of a new airport and the development of a space agency were signed on Saturday.
The two leaders also discussed regional problems, including the war in Sudan.
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