He resigned in 1907 to become an artist, studying at the John Hassall School of Art. Unsuccessful at first, he worked as an electrical engineer. Working this capacity for the Old Memorial Theatre, Stratford, brought him into acquaintance with Marie Corelli, who introduced him to Thomas Lipton, a connection that led to commissions to draw advertising sketches for Lipton tea, Player's cigarettes, Keene's mustard, and Beecham's Pills.
In 1914 he joined the Royal Warwickshire Regiment and served with a machine gun unit in France until 1915, when he was hospitalised with shell shock and hearing damage sustained during the Second Battle of Ypres. Posted to the 34th Division headquarters on Salisbury Plain, he developed his humorous series for the Bystander about life in the trenches, featuring "Old Bill", a curmudgeonly soldier with trademark walrus moustache and balaclava. Many of his cartoons from this period were collected in Fragments From France (1914) and the autobiographical Bullets & Billets (1916).
Despite the immense popularity with the troops and massive sales increase for the Bystander, initially there were objections to the "vulgar caricature". Nevertheless, their success in raising morale led to Bairnsfather's promotion and receipt of a War Office appointment to draw similar cartoons for other Allies forces.
In World War II, he continued Old Bill work, but was not asked to help with the British war effort. Instead, he became official cartoonist to the American forces in Europe, contributing to Stars and Stripes and Yank, whilst residing at Cresswell House in Clun, Shropshire. He also drew cartoons at American bases and nose art on aircraft. His works are considered to have influenced artists such as Bill Mauldin.
He died in 1959 of complications of bladder cancer. In later life, he had found himself typecast as the creator of Old Bill, and his Times obituary concluded of his career that he was "fortunate in possessing a talent ... which suited almost to the point of genius one particular moment and one particular set of circumstances; and he was unfortunate in that he was never able to adapt, at all happily, his talent to new times and new circumstances".