St Luke's won the brief to help the publisher reach a new target audience of younger readers in a pitch against another undisclosed agency.
Mills & Boon sells more than 7m books in the UK, but has not run any advertising for six years.
This year it has been celebrating its 100th anniversary, for which it designed centenary covers in-house.
Liz Little, business development director at St Luke's, said: "It is not every day that you get to work with a client listed in the Oxford English Dictionary.
"We look forward to working with Mills & Boon to set a new agenda for the brand and activate their growing community of readers."