After Zelenskiy, 43-year-old Kuleba is the best-known face of Ukraine overseas, meeting leaders around the world and lobbying for military and political support in fluent English.
More resignations and appointments are expected over the coming days after five ministers stepped down on Tuesday, in what a senior Zelenskiy ally cast as the start of a government "reset" before the cold autumn and winter seasons.
Ukrainian MPs have expected major changes in the government since the summer began. (AP PHOTO)
Kuleba's resignation letter was posted on Facebook on Wednesday by the Speaker of parliament, Ruslan Stefanchuk.
Zelenskiy has said changes to the government were necessary to achieve the results required by Ukraine.
"Autumn will be extremely important for Ukraine. And our state institutions should be configured so that Ukraine achieves all the results that we need - for all of us," he said on Tuesday.
Russian forces are advancing in the east of Ukraine while Ukrainian troops have made a bold incursion into Russia's Kursk region.
Moscow has intensified drone and missile attacks in recent weeks and Kyiv launched a mass drone attack on Russia's energy infrastructure at the weekend.
On Tuesday, at least 50 people, including soldiers, were killed by two missiles in the central Ukrainian town of Poltava in the deadliest single attack of the war this year.
Later in September, Zelenskiy travels to the United States, where he hopes to present a "victory plan" to US President Joe Biden, a key ally.
The Kremlin said that government changes in Ukraine would not affect a peace negotiation process in any way, although such talks appear a distant prospect with the two warring parties far apart in their objectives.
Russia has stepped up its long-range missile strikes on Ukraine. (AP PHOTO)
According to MP Yaroslav Zheleznyak, parliamentary committees would consider the resignations and then parliament would vote on them in what is usually a formality.
The new appointments are likely to be approved as soon as Thursday.
Zelenskiy is expected to nominate his candidate for a new foreign minister on Wednesday, with first deputy foreign minister Andrii Sybiha among the frontrunners.
On Tuesday, Strategic Industries Minister Oleksandr Kamyshin, Deputy Prime Minister Olha Stefanishyna and the justice, environment and reintegration ministers stepped down.
MPs and political analysts have expected major changes in the government since the summer began.
Prime Minister Denys Shmyhal has suggested the possibility of streamlining the government and folding several portfolios into one ministry.
At least five portfolios have been vacant since ministers were fired or resigned earlier this year, including the important agriculture and infrastructure ministries.
Opposition MP Iryna Herashchenko said: "It's a government without ministers ... an intellectual and personnel crisis that the authorities are closing their eyes to".
She called for a government of national unity that would end the tight grip on the reins of power held by Zelenskiy's political team.
