Tens of thousands of people poured into the city waving the region's independence flag and brandishing the colours red and yellow.
This year's march aimed to be the biggest ever - and a protest against the Spanish government's tax laws.
Catalonia wants Madrid to review its tax agreement and provide a bailout.
The size of the turnout for the rally, which is held annually on 11 September to mark the Siege of Barcelona 300 years ago, forced organisers to change its route.
Alfred Bosch, an MP from the Republican left of Catalonia, told the BBC: "All the flags I can see are the pro-independence flags of Catalonia with the lonely star right in the middle of the triangle.
"And everybody is wearing these flags. I have never seen so many pro-independence flags in my all life."
Protester Teresa Cabanes told Reuters: "This is a blow for the government. People like me came from everywhere. I don't think they were expecting something as big."
The huge volume of people overwhelmed the mobile phone network, which shut down for hours as a result, reports say.
Fiscal autonomy Spain's economic crisis, which has left one out of four people unemployed, has sharpened Catalonia's demand for fiscal independence from Spain, as well as political autonomy.
Catalonia, which is Spain's wealthiest region and represents a fifth of the Spanish economy, wants to be able to raise its own taxes and spend them.
Last month, Catalonia demanded a bailout from Madrid of 5bn euros (£4bn), on the basis that it believes the central government owes the region that much in overpaid taxes.
But, as with the rest of Spain, the region faces big economic challenges.
Catalonia has to take out 13bn euros (£10bn) in loans this year to refinance maturing debt, on top of funding its deficit for the current year.
The BBC's Madrid correspondent, Tom Burridge, also says economists have warned that the Catalan government has barely enough money to pay its public sector workers.
Regional bailouts Pro-autonomy leaders claim Catalonia pays a disproportionate level of taxes to Madrid in relation to the funding it receives.
Spain's Prime Minister Mariano Rajoy has said fiscal independence for Catalonia would achieve nothing in the country's overall battle against economic collapse.
Mr Rajoy and Catalonia's regional leader, Artur Mas, are due meet on 20 September.
Spain's struggling economy has declined for three consecutive quarters as it continues to suffer from the effects of its property bust caused by the financial crisis.
Other regions have appealed to the government for bailouts. The latest, Andalusia, asked for an immediate injection of 1bn euros (£800m) last week.
Valencia and Murcia have also requested bailouts in recent weeks.