It will be the first time the two cities' principal airports have been connected by air.
It comes two weeks after the airline added Krakow and Madrid to its winter schedule from Glasgow, increasing the number of routes to 17, and 23 in summer 2018.
The expansion - along with summer growth - is expected to increase the number of Ryanair passengers at Glasgow by nearly one quarter to 2.4 million a year.
In the past, Ryanair flew between Prestwick in Ayrshire and a secondary Frankfurt airport about 90 minutes from the city.
Glasgow Airport managing director Amanda McMillan said: "The introduction of Ryanair’s direct service to Frankfurt is a first for Glasgow Airport.
"This daily service will link two cities with much in common and further strengthen our European connectivity.
"Frankfurt is one of the world's leading financial hubs and home to the European Central Bank, while Glasgow is often cited as Scotland’s economic powerhouse."