The X1 commuter link from Hamilton will end on 27 October, the operator confirmed to The Scotsman.
The move angered some passengers.
Annual season ticket holder Ross Stirling tweeted: "The bus is constantly busy. Particularly for people commuting for office hours. You are changing people's commute from a 45min/1hr to a nearly 2 hour commute.
"I buy a yearly pass on the provision of using the x1 express. I do not want to spend that much money if there is no express replacement."
But First Glasgow commercial director Graeme Macfarlan said: “The Service X1 is a route that has been in decline for a number of years in terms of passenger numbers, despite a number of efforts to make the route attractive to service users.
“This is due to a number of factors such as increased congestion on the M74 which slows down journey times quite dramatically and increasing competition from the subsidised local rail network in Hamilton connecting to Glasgow.
“These have led to an overall decline in bus patronage.
“The hope with the service was that we may in time see a boost to passenger numbers.
“Unfortunately, this has not transpired and in fact passenger levels have now fallen to a level that makes the route unsustainable on a commercial basis.
“Therefore, in our latest network changes, having exhausted all efforts to boost the service, we have now taken the difficult decision to cease the service from operation.
“However, we have introduced the new 225 service which will cover part of the route between Little Earnock and Hamilton Palace Retail Park.
“Customers can also still continue to catch connections to Glasgow via our 267 and 255 services that serve the same area.”
First is also replacing its 19A service between Glasgow and Robroyston with a “faster and more direct” new X2 service via the M80 & M8, operating hourly between Monday and Saturday.
The operator said it was also increasing the frequency of its 19 service between Easterhouse and Glasgow from every 30 to 20 minutes due to an increased demand.
However, it is withdrawing its service 38/A/B/C/E between Glasgow Fort and Easterhouse due to low patronage.