Fast-rising temperatures have melted snow and ice, and along with heavy rains have caused a number of major rivers that cross Russia and Kazakhstan to overflow.
"Sirens are sounding in the city. This is not an exercise," Orenburg Mayor Sergei Salmin said on Telegram.
"Mass evacuations are ongoing," he said. "The situation is critical, do not waste time," he said, calling on people in several city districts to evacuate.
The Ural river has flooded much of Orsk, and Orenburg -- the regional capital -- has been preparing for the peak of the rising water.
The city has a population of some 550,000 people.
"In the last 10 hours the level of water on the Ural river rose by 40 centimetres (15.7 inches)," Salmin said, describing the situation as "dangerous".
Authorities have said that around 2,500 Orenburg houses have been affected by the water and almost 5,000 allotments.
Images on Russian state media showed an alley leading up to a monument that marks the border between Europe and Asia flooded, with lamp-posts partly submerged. They also showed water reaching many houses.
In Western Siberia, the Ishim river has also risen to dangerous levels, according to authorities in the Tyumen region. Officials have predicted that the Ishim and Tobol rivers will only reach a peak level around April 23-25.
A regional official, Sergey Balykin, told the RIA Novosti state news agency that the peak in Orenburg would come only on Friday or Saturday.
Russia has evacuated around 10,000 people from rising water, mostly from the Orenburg region.
Several villages have also been evacuated in the Kurgan and Tomsk regions further east.
Authorities said however that conditions had improved in Orsk, which was badly hit after dam breached. Officials said water levels were falling again.
Kazakhstan has evacuated more than 96,000 people, with the city of Petropavlovsk also bracing for the worst of the flooding.
No direct link has been made between the floods and global warming. But experts say the higher temperatures across the planet will cause the heavy rains blamed for the flooding.
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