The MV Brave Commander departed from the Black Sea port of Pivdennyi and will sail to Djibouti "for delivery to Ethiopia", the infrastructure ministry said on Telegram.
The ship is loaded with 23,000 tonnes of wheat.
It is the first ship chartered by the UN World Food Programme (WFP) to leave Ukraine since the war began in February.
The government has said it is hoping there will be two or three similar shipments soon.
Ukraine and Russia are two of the world's biggest grain exporters.
Kyiv and Moscow agreed a deal brokered by the UN and Turkey last month to unblock Black Sea grain deliveries after Russia's invasion.
The agreement lifted a Russian blockade of Ukraine's ports and established safe corridors through the naval mines laid by Kyiv.
The first commercial ship carrying grain left on August 1.
The WFP says a record 345 million people in 82 countries face acute food insecurity and up to 50 million people in 45 countries are on the brink of famine and risk being tipped over the edge without humanitarian support.
"We are definitely planning other ships to leave the ports of Ukraine, to help people around the world," Marianne Ward, WFP deputy country director in Ukraine, told journalists earlier while the ship was being loaded at the weekend.
"This should just be the first of many humanitarian ships to leave the ports," she said.
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