Marine traffic sites showed the MV Brave Commander taking its cargo of 23,000 tonnes of wheat through the heart of Istanbul after leaving the Ukrainian port of Pivdennyi on Tuesday.
The Turkish coastguard expect the Lebanese-flagged vessel to reach the Sea of Marmara on the strait's southern edge late on Wednesday, before sailing to Djibouti next week.
The grain will then be loaded on to lorries and delivered to Ethiopia under the UN World Food Programme, which is funded largely by the US.
"Getting the Black Sea ports open is the single most important thing we can do right now to help the world's hungry," WFP executive director David Beasley said.
"It will take more than grain ships out of Ukraine to stop world hunger, but with Ukrainian grain back on global markets we have a chance to stop this global food crisis from spiralling even further."
Russia began its invasion of Ukraine in February and the conflict has contributed to a food crisis in some of the poorest parts of the world.
The WFP, which is heavily dependent on wheat from south-eastern Ukraine, estimates that a record 345 million people face "acute food insecurity" in 82 countries.
It said 45 million were "right on the edge of famine".
A deal brokered last month by the UN and Turkey has allowed the first shipments of grain to begin to travel along a safe corridor through mines laid by Ukraine.
Almost all of the first shipments carried corn and other food supplies stored in Ukrainian ports and silos when the Russian invasion began.
The first small commercial shipment of wartime Ukrainian wheat arrived in Turkey last week.
The deal will top the agenda when Ukrainian President Volodymyr Zelenskyy hosts Turkish President Recep Tayyip Erdogan and UN chief Antonio Guterres in the western city of Lviv on Thursday.