The bus had around 20 passengers onboard when the vehicle left the road in the townland of Killogeenaghan, Moate at around 5.30pm.
Some of the passengers were taken to hospital to be treated for non-life threatening injuries, gardaí said.
The driver (55) after the vehicle left the road and collided with a ditch.
He was removed from the scene to the Midland Regional Hospital, Tullamore, in a serious condition and later died. A post-mortem examination will take place in due course.
Stephen Kent, Chief Executive Officer, Bus Éireann said: “This is a very sad event, affecting everyone in Bus Éireann. Our thoughts and deepest sympathies are with the family and friends of our colleague who received the worst possible news last night.
"We thank the emergency services for their work and their assistance to our colleague and to all the passengers affected by this difficult experience.
“The bus was travelling from Athlone to Drogheda, carrying approximately 20 passengers. All passengers disembarked safely, with no major injuries reported.
"A number of passengers were medically assessed at the scene and others transferred to local hospitals. Bus Éireann staff were on hand to organise onward travel for those who may have required it.
The road was closed following the accident a forensic collision investigators are conducting an examination this morning.
Mayor of the Athlone-Moate district, Vinny McCormack, said the tragedy was “heartbreaking” for the driver’s family, leaving the community of Moate shocked.
“It is an absolute terrible tragedy and our thoughts are of course with the driver and all of his family at this absolute terrible time,” he said.
“Thankfully there were no other serious injuries in the incident..
“It is a huge shock to the community and Bus Éireann has a great track record in terms of safety so obviously incidents like this with the company are very rare.
“It is so sad that an experienced driver was in such a tragic accident while he was just doing his day to day job, and for something like that to strike while he was just trying to get from A to B is heartbreaking.”
Fine Gael Councillor John Dolan, who lives close to the scene of the incident, said that it is such a tragedy for the area.
“I would be familiar with where it happened, it is just down the road from me,” he said.
“Unfortunately, the driver has passed away, our sympathies go out to his family, he was only a young man.
“It is a such a tragedy in the area but the only good thing is that no one else on the bus was killed or injured but a very sad time for the driver and his family.”
Gardaí are appealing for witnesses to come forward and any road users with video footage (including dash cam) are asked to make this available to them.
Anyone with information is asked to contact Athlone Garda Station (090) 649 8550, the Garda Confidential Line on 1800 666 111 or any garda station.