Motorists faced delays between South Brent and Totnes after a lorry full of fish shed its load onto the road.
The road was closed in both directions and traffic was “very slow” in the area.
Devon and Cornwall Police advised drivers to exercise caution and expect delays.
The road reopened around two hours later at about 7pm and officers say traffic eased shortly after.
A force spokesperson said: “The A385 was closed both ways, with very slow traffic due to a shed load of fish between Culver Lane in Rattery and the Tigley turn-off.
“The fish have now been cleared, with traffic easing and the road reopened.”
Lorry driver Michael Bettell said: “I was on my way back home to Plymouth from Torquay when I passed this unfortunate driver and the spilt load.
“It looked like two or three crates of fish and the pallet truck had fallen out the back doors of the lorry.
“Luckily I managed to get past before the police shut the road to have it cleared.”
Another witness told Devon Live that they saw “sardine-sized” fish all over the carriageway.
“It was quite a big truck and it looked like the pallets had fallen out of the back of the wagon along with one of those mobile forklifts that fit on the back of a truck,” they said.
“It appeared to be sardine-sized fish all over the road.”
Footage of the road can be seen below: