Hundreds of activists attacked police with bamboo sticks as they attempted to prevent them from marching towards the presidential office.
Protesters attempted to topple buses police were using to block the steets, and police responded by firing water cannons.
Several police officers were wounded in Wednesday's clashes, the AFP news agency reported.
Police said about 70,000 people, including 13,000 farmers, rallied in a plaza in central Seoul on the third consecutive day of protests against the agreement.
The authorities sealed off the centre of Seoul for hours, searching protesters and seizing sticks from them.
"Stop the US-South Korean FTA", read a large banner carried by protesters marching towards Seoul's city hall.
Miles away from the rally, US and South Korean negotiators continued talks on striking a free-trade agreement.
The pact, if agreed, would be the biggest US free-trade deal since the North American Free Trade Agreement in 1994.
The agreement has been criticised by trade unions and farmers' groups, who are against measures that include cheaper US imports.