Lines were reported at polling stations across the South End as voters cast ballots for U.S. House and Senate seats, Governor, state senate and other state-level positions on Tuesday, November 6. Two changes of the guard were officially ratified in the general election, namely the September 4 primary upsets of city councilor at large Ayanna Pressley over longtime incumbents Michael Capuano for the 7th district House of Representatives seat and Jon Santiago's victory for the 9th Suffolk District state house seat occupied by Byron Rushing since 1983.

Other races yielded more expected results, with U.S. Senator Elizabeth Warren retaining her seat against Republican challenger Geoffrey Diehl; the handy re-election of governor Charlie Baker; attorney general Maura Healey; secretary of state William Galvin; state auditor Suzanne Bump and treasurer Deb Goldberg. While Baker took an early, approximately two-to-one statewide lead against Democratic challenger, Jay Gonzalez, who conceded shortly after poll closing, Gonzalez actually bested Baker in Boston, winning 51 per cent of the city's vote versus Baker's 49 per cent.

Boston voters decided on three ballot questions: Question 1, which proposed a state-mandated ratio of nurses to hospital patients; question 2, which would establish a volunteer commission from Massachusetts to advocate for a constitutional amendment to limit corporate election spending by overturning the 2010 Supreme Court ruling, Citizens United. Question 3 was a referendum on a 2016 Massachusetts law banning discrimination against transgender persons in public accommodations, with a Yes vote upholding the discrimination ban and a No vote rescinding it. Question 1 had nurses' groups on both sides of the issue, but on November 6, it failed statewide by 70 per cent and in Boston by 64 per cent. Question 2 passed by 71 per cent statewide and by 78 per cent in Boston. On Question 3, 68 per cent of voters said Yes statewide, and in Boston, 77 per cent of voters said Yes to uphold the anti-discrimination law.

Some South End voters were briefly confused and concerned when news outlets reported that a "South End" polling place was closed due to the delivery of an unknown white powder in an envelope holding an absentee ballot, bringing the Boston Fire Department out to investigate. The polling place was located at 735 Shawmut Avenue, near Ruggles Street in Roxbury, and BFD investigators quickly determined that the white powder was baking soda and re-opened the location for voting.