Footage on social media shows the shopping centre in Kremenchuk, which both the Ukrainian President and his aide claims was hit with a Russian missile, completely ablaze.
The president’s aide Mykhailo Podolyak said on Twitter: “Russia is deliberately firing a rocket into a shopping mall with more than a thousand civilians.
“Just in the middle of the day. Just because he wants to kill.
“To fill everything with Ukrainian blood. Russia is a terrorist state.
“Russia is waging the most disgusting war.”
According to the deputy head of the Ukrainian presidential office Kyrylo Tymoshenko, at least two people were killed and 20 were injured in the attack. Nine of these are in a serious condition, he says.
However, the number of confirmed dead is expected to rise significantly.
The cruel and brutal attack comes just a day after G7 leaders met in Bavaria to discuss their ongoing response to the Russian invasion of Ukraine.
Mr Zelensky added on Telegram: “The mall is on fire, firefighters are trying to extinguish the fire, the number of victims is impossible to imagine.”
He added that the building posed “no danger to the Russian army” and held “no strategic value” to Putin’s forces.
He went on to add: “People only wanted to live a normal life, which is what angers the occupiers so much.
“Out of helplessness, Russia continues to hit ordinary people. It is vain to expect it to be reasonable or humane.”
The city’s mayor Vitaliy Meletskiy said the strike on the “very crowded” building had caused deaths and injuries, but gave no figures.
Videos posted online show large crowds outside the burning shopping centre.
Kremenchuk once had a population of 217,000 before Russia’s invasion of Ukraine.
It lies on the Dnipro river in the region of Poltava, and is the site of Ukraine’s biggest oil refinery.
There has been no immediate comment from Russia, which denies deliberately targeting civilians.
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The attack comes as Putin continues his all-out assault on the eastern Luhansk region.
Luhansk Governor Serhiy Haidai claims Russian forces are “pouring fire” on the city of Lysychansk from the ground and air.
Mr Haidai told the Associated Press: “They’re pouring fire on the city both from the air and from the ground.
“After the takeover of Sievierodonetsk, the enemy army has concentrated all its forces on capturing (our) last stronghold in the Luhansk region: Lysychansk.”
He added the Russians were “destroying everything that their artillery and multiple rocket launchers can reach.”