Protests by an ethnic Madhesi group as well as violence and clashes by other rebel outfits across the fertile Madhesh, also known as the Terai, have left scores of people dead this year.
The turmoil has dealt a blow to a 2006 peace process that has seen former Maoist rebels join the political mainstream.
Madhesis say they were discriminated against by the hill-dominated ruling elites and are demanding better representation in the parliament and government jobs, including the army and police.
The resignations by Mahanta Thakur, the science and technology minister and a member of Prime Minister Girija Prasad Koirala's Nepali Congress party, and the lawmakers from other political groups comes amid criticism that the multi-party government had failed to control the violence in the Terai region bordering India.
"The state has devalued the aspirations of the Madhesi people -=85 and (the ruling) political parties have ignored calls for their rights," they said in a statement read out to reporters.
They also vowed to launch a "peaceful struggle" to end discrimination in the region and press for the Madhesi demands.
There was no immediate comment from the government.
Terai is impoverished Nepal's bread basket and home to nearly half of its 26.4 million people.
Madhesis are ethnically, culturally and linguistically closer to people living in neighbouring India than to Nepalis living in the mountains.
(Reporting by Gopal Sharma; Editing by Krittivas Mukherjee and Alex Richardson)
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