The activists said troops backed by armoured vehicles had entered the Midan district to try to dislodge rebels.
Witnesses say this appears to be the biggest military deployment in the capital in the 16-month uprising.
Meanwhile, Russia said Western attempts to get Moscow to discuss sanctions contained "elements of blackmail".
Monday's clashes appeared to be the heaviest fighting in Damascus in the 17-month uprising against the rule of President Bashar al-Assad, activists said.
The BBC's Jim Muir says the violence seems to be creeping ever closer to the heart of the capital and the centre of the government's power.
1. Syrian-led political process to address the aspirations and concerns of the Syrian people
2. End to violence by all sides; army troops to stop using heavy weapons and withdraw to barracks
3. Parties to allow humanitarian aid
4. Authorities to free political detainees
5. Authorities to ensure freedom of movement for journalists
6. Authorities to allow peaceful demonstrations
The armoured troop carriers took up positions on the main roads in Midan, which is a mainly Sunni district.
The Syrian Observatory for Human Rights said armour had not previously been deployed in Midan.
Its director, Rami Abdel Rahman, told Agence France-Presse: "Before, the security forces were deployed to suppress protests. Now, we have army troops engaged in combat."
He added: "[It has] never been this intense."
One resident, who lives in the south of the city, told the BBC's Newshour there was a lot of tension, with people scared and nervous, and it was becoming difficult to travel.
He said: "It's mainly in the southern parts of the city which are effectively besieged at the moment. There were very few people on the streets, just totally different from how the city is normally.
"The feeling is, among people around me, is that it's our turn now. We are really feeling this. That this is the final fight, building up to who wins control of the regime."
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One activist told AFP the army was trying to storm Midan from two sides, adding: "There are many injured and some killed. We need blood donations."
Two days of fighting have also seen clashes in the Tadhamon, Jobar and Kfar Sousa districts.
Video footage on social media websites purported to show fighting in Kfar Sousa and Midan, with black smoke and the sound of gunfire.
However, the video cannot be verified. News reports from Syria are difficult to confirm as it severely restricts journalists' freedom of movement.
The pro-government al-Watan newspaper said "terrorist groups" were seeking to launch "the great Damascus battle".
Meanwhile diplomatic moves are continuing ahead of Friday, the deadline for the end of the UN observer mission's mandate in Syria.
There have been mixed signals from Moscow in recent weeks, with some suggestions that Russia's support for the Syrian government may be waning.
Today, though, Sergei Lavrov dispelled the rumours. Just a few minutes into his press conference, it became obvious that Moscow's position hadn't changed an inch. Russia refuses to lay the principal blame for the violence on President Assad; it is up to both sides in the conflict to stop fighting and start negotiating.
The Russians are clearly fed up of Western criticism that Moscow could - but won't - push President Assad from power. The message from Mr Lavrov: it's "unrealistic" to expect Russia to do that, because there are still many Syrians who support President Assad.
And when Russia's foreign minister accused the West of trying to "blackmail" Russia into supporting a tougher UN Security Council Resolution, he revealed the chasm between East and West over Syria. Judging from Mr Lavrov's words, Kofi Annan will struggle to persuade Moscow to adopt a tougher tone with Damascus.
Russian Foreign Minister Sergei Lavrov said the West had threatened to end the mission if Moscow opposed its draft resolution, which threatens more sanctions.
Mr Lavrov said the attempts contained "elements of blackmail".
Moscow has circulated its own draft resolution calling for the extension of the mandate but without a threat of sanctions.
UN and Arab League special envoy for Syria Kofi Annan is due in Moscow, and is expected to urge Russia to put more pressure on Syria's leaders to begin a political transition.
Russia has strong ties with Syria and has vetoed foreign intervention calls.
It was "not right" to say that pressure should only be brought on the government of President Assad and not the opposition to end the conflict, Mr Lavrov said.
"We do not support Assad," he said. "We support what has been agreed by all sides."
He said it was unrealistic to expect Russia to persuade Mr Assad to step down.
Mr Annan is expected to meet Russian President Vladimir Putin and Mr Lavrov during two days of talks.
UN Secretary General Ban Ki-moon is also expected to raise the Syrian issue with Chinese leaders when he arrives in Beijing for a China-Africa summit. China has joined Russia in vetoing several Western-backed UN draft resolutions calling for tougher action.
Separately Morocco has become the latest of many countries in the region and around the world to expel its Syrian ambassador.
The country's foreign ministry said in a statement that Nabih Ismail had been declared persona non grata.
Shortly afterwards Syria expelled Morocco's ambassador in Damascus.
Some 16,000 people are thought to have been killed since the uprising against Mr Assad's regime began in March 2011.
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