The attackers struck at midday, opening fire on a restaurant before getting into a car and blowing themselves up at a nearby security checkpoint, officials said.
Security sources said the attackers were disguised as members of the Hashed al-Shaabi, a mainly Shiite paramilitary alliance which has fought alongside the army and police against the Islamic State jihadist group in northern Iraq.
The toll from the attacks was 52 dead and 91 wounded, said Abdel Hussein al-Jabri, deputy health chief for the mainly Shiite province of Dhiqar of which Nasiriyah is the capital.
Jabri told AFP that many of the wounded were in serious condition.
The area targeted is used by Shiite pilgrims and visitors from neighbouring Iran headed for the holy cities of Najaf and Karbala further north, although Dhiqar has previously been spared the worst of Iraq's violence.
It said several suicide bombers had staged the assault on a restaurant and a security checkpoint, killing "dozens of Shiites".
The toll makes it the deadliest IS attack in Iraq since pro-government forces drove the jihadists out of second city Mosul in July.
The Sunni extremist group regularly stages attacks in Iraq, where it has also lost swathes of territory to US-backed pro-government forces.
Today's attacks come as Iraqi forces backed by tribal fighters close in one of the last IS bastions in the country: the Al-Qaim area on the border with war-ravaged Syria.
The group's only other stronghold is Hawija, in Kirkuk province some 300 kilometres north of Baghdad.
IS has suffered a string of defeats on the battlefields of Iraq and Syria, leaving in tatters the cross-border "caliphate" it declared in 2014.
But any military offensive in Hawija is expected to be postponed due to a planned referendum on Kurdish independence.
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