After apprenticing as a teenage assistant to T.A. Dorgan, Gross's first comic strip was Phool Phan Phables for the New York Journal, begun when he was 20, featuring a rabid sports fan named George Phan. It was one of several shortlived comic strips (and other undertakings, including his first animated film) before his first success, Gross Exaggerations, which began as an illustrated column in the New York World. Its Yinglish vocabulary would set the tone for much of Gross's work, as would its reworkings of well-known tales, as in "Nize ferry-tail from Elledin witt de wanderful lemp", and "Jack witt de binn stuck" (see Jack and the Beanstalk). These were gathered in a 1926 book Nize Baby, which then evolved into a Sunday newspaper color comic strip.
Also in 1926, he published Hiawatta witt no odder poems, a 40-page parody of Longfellow's Hiawatha, each, in the words of Jim Vadeboncoeur, Jr., "with a barely decipherable stanza and a drawing which only sometimes helped."

In 1927 he followed up with De Night in De Front From Chreesmas (see The Night Before Christmas) and Dunt Esk. In 1928 he published Famous Fimmales Witt Odder Ewents From Heestory. In 1930, he published the wordless He Done Her Wrong: The Great American Novel and Not a Word in It — No Music, Too, a comic novel in woodcuts, nearly 300 pages long, and comparable in scale to silent films such as those in the series The Perils of Pauline; it also resembled (and parodied) the "silent novels" of Lynd Ward. (It is not quite wordless, because there are some lettered signs.) It has been reprinted several times, including in 1983 as Hearts of Gold and in 2005, by Fantagraphics, under its original title.
Starting in 1931 he worked for the Hearst chain, doing various comic strips, including Count Screwlooose of Tooloose, Dave's Delicatessen, Babbling Brooks, Otto and Blotto, and That's My Pop! (later a radio show), with his strips' vocabulary moving somewhat closer to standard English over time, while maintaining some Yiddish touches. He also published two books in 1936, Pasha The Persian and What's This?
In 1939, he returned briefly to animated film, making two cartoons, "Jitterbug Follies" and "Wanted: No Master", featuring Count Screwloose (voiced by Mel Blanc, who couldn't take a screen credit because of his Warner Bros. contract) for MGM's.
In 1945, the year of his book Dear Dollink, he suffered a heart attack and went into semi-retirement. His last book was I Shouda Ate the Eclair (published 1946), in which one Mr. Figgits nearly starts World War III because he refuses to eat a chocolate eclair. In 1946–47, his work appeared in the short-lived comic book Picture News.
In 1950, two of his earlier books were combined as Hiawatta and De Night in De Front From Chreesmas.