The destination, which was previously only accessible from London, will now be open to travellers from the north of the UK year-round.
Flights began this month and will increase to twice daily on weekdays and once a day at weekends from 1 October.
Vincent Hodder, Flybe chief revenue officer, said: "We are delighted to be launching our first flights between Manchester and Luxembourg today. Not only is this a first for Flybe, it is also now the only direct route offered to Luxembourg City outside of London. It is a fantastic destination for both business and leisure travellers alike. We have scheduled flight times to make day trips a real possibility as well as helping business travellers save on expensive hotel costs."
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