Scores of demonstrators had blocked the highway between the provincial capital of Jalalabad and a major Pakistan border crossing in protest over the appointment of a local police chief when the suicide bomber blew himself up.
Last week, US Secretary of Defense James Mattis made an unexpected trip to Afghanistan as the US tries to make headway in the country after 17 years of war.
The attack came hours after smaller bombs targeted at least three schools in and around Jalalabad, killing a boy and wounding four people.
Officials have warned violence is likely to intensify ahead of parliamentary elections next month and a presidential election in April.
"All people killed were civilians in the attack", Ataullah Khogyani, the governor's spokesman, told Al Jazeera. The casualty toll increased overnight as a number of critically wounded protesters died from their injuries. The Taliban issued a statement denying involvement.
The fighting has tempered optimism that had been tentatively growing as Afghan and worldwide players ratchet up efforts to convince the Taliban to negotiate an end to the 17-year conflict. Two other blasts took place in Bihsud district early morning.
A 12-year-old boy was killed and several children and adults were wounded by a secondary blast that hit first responders and families rushing to the scene of the explosion.
In the northern province of Sar-e Pul, hundreds of armed men assembled to boost the city's defences as security forces fought to push the Taliban back from the city centre, said Zabihullah Amani, the provincial governor's spokesman.
Ghulam Mohammad Balkhi, deputy spokesman for the Afghan army's 209 Corps, said at least 30 Taliban fighters were killed in the joint operation.