MacDonald grew up in Point Anne, Ontario, east of Belleville on a farm.
MacDonald’s earliest images were of the land, the water, and animals on that farm. This creativity developed, at an early age, and was encouraged by teachers and family, producing a seasoned oil painter before any formal classes began. His free, loose, and semi-impressionistic style is filled with rural scenes of mills and farms with livestock as well as rivers and lakes on which boats float and dock, in the Group of Seven genre. MacDonald was also an excellent portrait painter. Manly MacDonald, began his formal training at the Albright Art School in Buffalo, New York, in 1910, followed by two years at the Boston Museum of Fine Arts.
In 1914 MacDonald returned to Canada and attended the Ontario College of Art, which would have a profound impact on his life and painting. A Royal Canadian Travelling Scholarship took him and his new bride Beverly to Europe, sketching and painting war sites in 1920. This led, to a commission by the Canadian Federal government to paint scenes of women working in the fields, gathering food for a nation at the end of the Great War. That same year MacDonald was elected a member of the Ontario Society of Artists (OSA), and an Associate Member of the Royal Canadian Academy (ARCA). In 1951 MacDonald resigned from OSA, after thirty years as a member, in protest over that society's emphasis on what MacDonald called "Modern art".
MacDonald was a founding member of the Ontario Institute of Painters (OIP) in 1958, and taught at the Ontario College of Art from 1946 to the mid-60's.