Water is gushing towards Dadu district because of a breach in the Toori dam at upper Sindh.
In the past weeks all but four of Sindh's 23 districts have been deluged.
Aid agencies say more than eight million people who have left their homes need food and water.
Most of the floodwaters are pouring down from the Toori dam, which was washed away in August.
The breach has caused the waters of the River Indus to split in two.One side is continuing to flow to the Arabian sea, while the other is going parallel to the Indus's natural course, wreaking a path of destruction.
This rogue flow of water has now reached Dadu district, and is pouring into Manchar, the country's largest freshwater lake.
It has swollen to the extent that it is now threatening to inundate those parts of the province which have so far escaped the disaster.
Residents, who had begun hoping the flood threat was now receding, are now fleeing their homes, with at least 350,000 on the move.
If Lake Manchar overflows, the waters could cut off access to the Indus highway, the area's main connection to the rest of the country.
Army engineers are trying to prevent this happening by plugging the breach at the Toori dam.
Their job has been severely hampered by fresh rains in northern Pakistan, which have given a new lease of life to the flooding.
More than 1,600 people have died and about 17 million of Pakistan's 166 million people have been affected by the disaster.