Pockets of fans threw flags and bottles at police at a major roundabout in the city, while revellers of all ages, decked out in red, white and blue, whistled and cheered for their side following their 2-1 loss against Spain.
As many as 50,000 people swarmed onto the main road that runs through Santiago to celebrate, local media estimated.
The post-match unrest had been quelled but more detentions could follow, said police, who have now made mass detentions in Santiago after each of the side's three World Cup games.
Friday's match comes almost four months after a devastating earthquake hammered south-central Chile and killed more than 500 people, and many Chileans feel the team's progress has lifted the national spirit.
New Conservative President Sebastian Pinera watched the game from the south-central coastal town of Iloca, which was battered by tsunamis triggered by the quake.
"We are incredibly proud of what the Chilean players are doing," Pinera said, clutching a national flag. "I want the team to know that they have the hopes of a nation resting on them, a nation that has suffered greatly from an earthquake and tsunamis."
"This time, history will be changed because the Chileans deserve it," he said.
Karen Troncoso, a 31-year-old hardware store cashier, dismissed the loss to Spain which had Chile midfielder Marco Estrada sent off in the 37th minute for a second yellow card after tripping Fernando Torres off the ball.
"It doesn't matter, we're happy anyway," she said. "We're in the World Cup, and we're showing that we can do it. It's helping the people who suffered most from the earthquake to be happy, and it unites us as a country."
Hours after the game, the streets of Santiago resounded with the ever-present din of vuvuzela horns and football songs.
Chile face Brazil on Monday.
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