Jonathan Forte hit the post for the visitors, who are six points above the bottom four, before Tareiq Holmes-Dennis sent an effort wide.
Oldham keeper Joel Coleman saved a David Worrall shot at the other end.
Main fired home after the hour mark as he latched on to Forte's pass to seal victory for the Latics.
Oldham have a sizeable cushion above the League One relegation places with three games left to play, while Southend remain in 13th place.

Storms smashed a hole in the sea wall alongside the line above the seafront in Dawlish, south Devon in 2014.
The railway line took two months to repair at an estimated cost of £1bn to the local economy.
Network Rail is consulting with Devon and Cornwall residents about the plans.
They include strengthening defences and cliffs, as well and building breakwaters to protect the line.
More on the coastal rail protection work, and other Devon and Cornwall news
Cliffs next to the line would be stabilised and reshaped so they are not as steep under the plans.
A total of £270m is allocated for spending on priority areas including around Dawlish between 2019 and 2024.
The line connects Devon and Cornwall with the rest of the UK.

Vikki Thompson, 21, was found dead in her cell at HMP Leeds in 2015 with a ligature around her neck.
Robert Steele told the hearing in Wakefield Miss Thompson wrote to him while in prison saying: "I know I'm going to do something silly."
Giving evidence he said: "I believe she shouldn't have been in a male prison."
More stories from across Yorkshire
The jury inquest was also told Miss Thompson, from Keighley, had repeatedly told prison and court escort staff that she would be "carried out in a box".
Mr Steele said he spoke to her on the phone while she was in prison and she told him she wanted to move to a women's prison that and her solicitors were waiting for her to make a formal application to the governor.
Mr Steele also said he received a letter from his partner which said: "I don't think I can last very long in here. I can't sleep at night. I just feel like I won't be here no more.
"I know I'm going to do something silly. I don't want to but I can't do this."
But, in a statement read to the court, Miss Thompson's mother Lisa Harrison said her daughter did not say she had a problem being in a men's prison.
"Vikki didn't like prison but who does?" Ms Harrison said. "She never said anything to me about it being the wrong prison for her."
The inquest heard Miss Thompson had identified as female since she was 10 years old but had never had any surgical or hormone treatment.
She did not have a Gender Recognition Certificate establishing her female identity so she was sent to a men's prison.
Coroner Jonathan Leach said the inquest would examine a number of issues including the suitability of the "prison accommodation".
The jury was told that after an extensive risk assessment process Miss Thompson was initially put in E-Wing rather than A-Wing, where vulnerable prisoners were housed, and placed on a one-hour suicide watch.
Mr Leach said this decision was taken because it was thought she might be under more risk on A-Wing due to the number of sex offenders there.
He said she was later allowed to move to A-Wing but was taunted by men in the segregation block below.
The inquest heard that on the day she died Miss Thompson had been seen watching TV at 19:00 GMT but at 20:00 she was spotted on the floor with the ligature round her neck and the alarm was raised.
The inquest, which is expected to last three weeks, continues
Oldham Athletic boosted their hopes of League One survival as Curtis Main's second-half goal sealed a vital three points against Southend United.
[NEXT_CONCEPT]
Protecting a key coastal railway track from rising sea levels and falling cliffs is going to cost about £650m, Network Rail has said.
[NEXT_CONCEPT]
The partner of a transgender woman found dead in a men's prison while on remand has told an inquest she did not want to be in a male jail.