About 1917, Keppard settled in Chicago, which would remain his home (except for briefly going to the East Coast to work with Tim Brymn's band about 1920). Soon after he had settled himself into the Chicago jazz scene, however, King Oliver became Chicago's "cornet king" and was said to have attracted crowds by "thrusting his horn out of a window and blowing Keppard down." Nevertheless, Keppard did well in finding continuous employment with a wide range of bandleaders, at one point leading his own group with Jimmie Noone on clarinet and Paul Barbarin on drums.

Keppard worked in Chicago both as a soloist and with the bands of Jimmie Noone, Johnny Dodds, Erskine Tate, Doc Cook (for several years), Don Pasqual, Lil Hardin Armstrong, Ollie Powers, and John Wycliffe, all of which were highly respected local bands. Keppard was one of the first to bring jazz to the West Coast.

Don Pasqual, who played reed instruments for Doc Cook for some time, had much to say about Keppard's contributions to Doc Cook's band:

Keppard really gave the band a lift and then we really went to town. Later, Andrew Hilaire and Johnny St. Cyr joined the band. Doc Cook seldom wrote out any special parts for Freddie Keppard but would just give him his head and while we were playing the arrangements Keppard would do anything he wanted.

— Don Pasqual

After he found steady employment in Chicago, Keppard's style helped create a demand for more New Orleans groups, paving the way for other New Orleans players seeking to migrate north. Throughout his travels, Keppard sent back clippings to his fellow musicians in New Orleans, encouraging other bands to take their chances on the cross-country circuits.