At least four blasts struck the southern Damascus suburb of Sayyida Zeinab, killing at least 83 people, state media said.
Earlier in Homs, 57 people, mainly civilians, were killed in a double car bombing, a monitoring group reported.
So-called Islamic State (IS) said it carried out the attacks in both cities.
Meanwhile, US Secretary of State John Kerry has said a "provisional agreement" has been reached with Russia on a partial truce in the conflict.
Both of Sunday's attacks targeted areas dominated by minorities within Islam reviled by the Sunni Muslim radicals of IS.
In Damascus, at least four explosions were reported in Sayyida Zeinab, the location of Syria's holiest Shia Muslim shrine, said to contain the grave of the Prophet Muhammad's granddaughter.
The state-run Sana news agency reported at least 83 dead and 178 wounded.
The Amaq news agency, which is linked to Islamic State, said IS militants had detonated a car bomb and then blown up explosive belts.
The district was hit by suicide attacks last month that left 71 people dead and which IS fighters also said they had carried out.
In Homs, the blasts happened in a predominantly Alawite district, the sect to which President Bashar al-Assad belongs.
Syrian state TV footage showed debris and mangled vehicles.
One of the early centres of the uprising against President Assad, Homs was once dubbed the "capital of the revolution".
But rebels left the city late last year under a ceasefire deal, leaving the city in government hands.
The UK-based Syrian Observatory for Human Rights monitoring group also said that at least 50 Islamic State fighters had been killed in an advance by government troops, backed by Russian air strikes, east of the northern city of Aleppo in the past 24 hours.
Meanwhile, Mr Kerry spoke optimistically about progress towards a possible ceasefire.
He had spoken to his Russian counterpart Sergei Lavrov, he said, and they had agreed on terms but details still needed to be worked out.
Earlier this month, world powers involved in Syria agreed to seek a "cessation of hostilities" but the Friday deadline has come and gone.
For his part, President Assad has said he hopes to be remembered as the man who "saved" Syria.
Asked by Spanish newspaper El Pais where he would see himself in 10 years' time, he said: "If Syria is safe and sound, and I'm the one who saved his country - that's my job now, that's my duty."
Mr Assad also said his army was close to encircling rebel-held parts of Aleppo, and were advancing on Raqqa, the main stronghold of IS fighters.
He said he was ready to implement a temporary truce as long as there were guarantees what he called "terrorists" would not use it to improve their positions.
Separately, Amnesty International has criticised Turkey for refusing entry to some Syrians wounded in the latest fighting, urging it to keep its border open.
Amnesty's crisis response director, Tirana Hassan, said: "Turkey's highly selective practice is appalling - only severely injured people are allowed entry to seek medical treatment while everyone else fleeing the violence is left unprotected."
Source: BBC News