While seeking a book publisher, Gonick received early support from Jacqueline Kennedy Onassis, who worked as an editor at Doubleday and championed The Cartoon History of the Universe's publication by the company.

His drawings resemble Bill Watterson's Calvin and Hobbes, Walt Kelly's Pogo, and René Goscinny and Albert Uderzo's Astérix.

Occasionally, as in the sequences on India in the second book, he mimics Gilbert Shelton's style from The Fabulous Furry Freak Brothers.

An Einstein-like Professor (representing Gonick's authorial voice) prepares to travel in his time machine to whatever place or era the chapter is about.

Any history book has a point of view, and Larry Gonick's might best be described as "humanist", but it is not written in the style of a didactic textbook.

Instead, Gonick fleshes out history into a long yarn, injecting characterization into historical personages, continually reporting gory anecdotes, and focusing on quirky details—all backed up by research—to enliven his subject.

But rather than relying upon an ordinary, typeset bibliography, Gonick sustains his unorthodox style and exuberant tone as the Professor takes the reader through a cartoon tour of his sources.

Some of these primary sources are national epics, cultural writings, or holy scriptures, such as Homer's Iliad, the Rig Veda of India, and the Bible.