Although the referendum is non-binding, a large "no" vote could torpedo plans to build the plant along with neighbors Estonia and Latvia.
Supporters say the new plant, which would be built by Japan's Hitachi, is needed to ensure the region's energy independence. But many Lithuanians fear that the project, which has an estimated 5 billion euro ($6 billion) price tag, will shackle the country of 3 million people with overbearing debt.
Others have safety concerns, especially in light of the earthquake and tsunami disaster at Japan's Fukushima nuclear plant last year.
"I do not want my country to become a playground for Lithuanian and Japanese nuclear business games. Let them have their own Fukushimas. We had already had one of our own — a disaster in Chernobyl," Danute Cekanaviciene, a 52-year-old designer, said in reference to the 1986 Soviet nuclear accident.
Lithuania, an ex-Soviet state, relies predominantly on Russian gas for energy. Energy prices increased 20 percent earlier this year, and utilities have warned that this winter will be the most expensive yet.
The most recent poll, which was taken in May, showed that two-thirds of Lithuanians opposed building a new atomic power plant.