[9][10] In addition to his editorial cartooning, in 1905 he was producing five regular comic strips: Little Sammy Sneeze, Dream of the Rarebit Fiend, Little Nemo in Slumberland, Hungry Henrietta, and A Pilgrim's Progress.

This is in contrast to the great variety of panel sizes and layouts displayed in McCay's earlier strip The Jungle Imps, and later much more prominently in Little Nemo.

[12] Sammy and McCay's other child protagonists differ from those of Outcault and other popular cartoonists, such as Rudolph Dirks and his rambunctious, pranking Katzenjammer Kids.

On occasion his sneezes have positive consequences, as when he frightens a stubborn mule to move out of the way of an oncoming train,[a] or foils a group of kidnappers.

"[17] McCay took the visual ideas he experimented with in Little Sammy Sneeze and Dream of the Rarebit Fiend[18] (also 1904)[16] and more fully explored them when he began Little Nemo the following year.

[18] While the technical dexterity Little Nemo draws the greatest share of attention among McCay's works, Katherine Roeder finds the formally lower-key Sammy Sneeze "tested the limits of visual representation and demonstrated the comic strip's potential as a vehicle for modernist experimentation".

[19] McCay was fond of breaking the fourth wall,[20] a well-known example of which is the September 24, 1905, episode: the gag unfolds according to formula, culminating in the destruction of the very panel borders of the comic strip itself.

[22] McCay was concerned with depicting the seldom-perceived minutiae of movement, though his was not the scientific curiosity found in the chronophotography of Eadweard Muybridge, Étienne-Jules Marey, and Georges Demenÿ.

Frost's incorporated the repetition of backgrounds inspired by chronophotography, and by the time of Sammy Sneeze had become a standard comic-strip trope—one comics historian Thierry Smolderen suggests McCay may have deliberately parodied.

These audiences may have seen the inevitable consequences for Sammy as a restoration of a natural social order, one that was left rent asunder in other comic strips.

[29] The strip's header declared to each side of the title "He just simply couldn't stop" and "He never knew when it was coming", and never strayed from the basic formula of build-up, release, and consequence.

McCay was to make use of such framing devices throughout his career, as in Little Nemo where the reader could rely on the protagonist awakening in the closing panel each week.

[33] McCay joined William Randolph Hearst's newspapers in 1911,[34] and Sammy made a reappearance in them on February 4, 1912, in a one-off strip titled "All at Once—Kerchoo!—He Sneezed".