Authorities in the district said the suspected shooter was killed by an armed civilian.
Tension has been surging in the region as Israel continues to pound the Gaza Strip more than four months after the Palestinian militant group Hamas attacked its towns.
"This attack reminds us that the entire country is a front and that the murderers, who come not only from Gaza, want to kill us all," said Prime Minister Benjamin Netanyahu. "We will continue to fight until total victory."
Israel's police commissioner Kobi Shabtai declined to respond to questions on the identity of the shooter, who was also killed, saying an investigation of the incident was still in preliminary stages.
Central district commander Avi Biton said an assailant had opened fire at a bus station near a junction in southern Israel early Friday afternoon, wounding six people. He said an armed civilian who was on site shot the suspect and police forces were searching the area to rule out the possibility of additional perpetrators.
The Magen David Adom ambulance service said two of the casualties had died and four others were transferred to hospitals for treatment with moderate to serious wounds.
National Security Minister Itamar Ben-Gvir said the incident "proves again that weapons save lives". He pledged to increase the distribution of firearms to civilians in the wake of the October 7 Hamas-led attack on Israel that has prompted Israelis to arm themselves in record numbers.
Israel's Gaza offensive has killed more than 28,700 Palestinians, according to Palestinian health authorities, laid much of the strip to waste and displaced most of its 2.3 million population.
Israel says its goal is to destroy Hamas after the group's fighters led an attack in which 1,200 people were killed and 253 taken hostage.
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