The yellow – “be aware” – alert is for up to 90mm of rain to fall on hills and 20-40mm on lower ground across the west and south west between Glencoe and Dumfries, including Glasgow.
It will be in force from 9pm on Saturday to 9am on Sunday.
The Met Office warned of potential disruption, including to travel.
The landslide-prone A83 Rest and Be Thankful pass in Argyll will be shut from 7pm on Saturday as a safety precaution.
Traffic will be diverted in convoys along the parallel single-track Old Military Road, further down the Glen Croe hillside.
The Met Office said: “A spell of persistent heavy rain, accompanied by fairly windy conditions, will set in across parts of south west and central Scotland on Saturday evening and last until Sunday morning.
"Rainfall accumulations of 20 to 40mm are expected quite widely, with perhaps as much as 70 to 90 falling in a few spots over the hills.”
BEAR Scotland, which maintains the A83 for Transport Scotland, said the road would be inspected on Sunday morning to see if it was safe to re-open
It said: “Wet weather is forecast to arrive in the region from late afternoon on Saturday and is expected to be at its most intense overnight into Sunday morning.
“With up to 60mm of rain possible over the weekend, and the increase in hillside saturation that will occur as a result, the decision has been taken to switch traffic from the A83 to the Old Military Road.”