The explosions in the cities of Tartus and Jableh were the first to target civilians in those areas in the course of Syria’s civil war, now in its sixth year.
The targets included bus stations and a hospital, and mark an escalation in the conflict as world powers struggle to restart peace talks in Geneva.
Several rounds of talks were held in the Swiss city earlier this year, with no breakthrough.
Syrian state media said at least one suicide bomber, followed by a car bomb, struck at a bus station in Tartus. More than 33 were killed and many injured, said an Interior Ministry official.
Separately, Syria news agency Sana reported that four explosions rocked Jableh, south of Latakia city.
The attacks included three rockets and a suicide bomber at the emergency entrance of the Jableh national hospital.
Russia keeps a naval base in Tartus and an air base in Latakia province. Insurgents maintain a presence in rural Latakia.
The co-ordinated and near-simultaneous attacks marked a major security breach of government strongholds that have remained calm throughout the war.
Tartus and Jableh are home to thousands of internally displaced people from violence-stricken areas across Syria.
The Syrian Observatory for Human Rights, an opposition monitoring group based in Britain, put the death toll at more than 100.
It said there were four explosions in Jableh, including three suicide bombings and one car bomb, and four in Tartus, including two suicide bombers and one car bomb.
In Jableh, dozens were killed when a car bomb exploded near a bus station, followed by a suicide bomber who detonated his explosive belt inside the station.
Two men blew themselves up at the electricity company and outside the emergency entrance of a city hospital.
Dozens more were killed in Tartus when a car bomb went off in the bus station, and two men blew themselves up when people gathered, according to the observatory.
Syrian cabinet minister Omran al-Zoubi said: “We will not be deterred... we will use everything we have to fight the terrorists.”
A news agency linked with IS said its militants were behind the multiple attacks.