No in most style guides — "of" is lowercase in AP Style, Chicago Style, and MLA Style.
"Of" appears in a vast number of titles and is one of the words most frequently lowercased in standard title case. It is lowercase in AP Style, Chicago Style, MLA Style, and AMA Style, but capitalized in NYT Style.
"Of" appears in many famous titles — "The Sound of Music," "Lord of the Flies," "The Heart of Darkness" — and is consistently lowercase in the published versions because book publishers follow Chicago Style.
The NYT Style capitalization of "of" is one of the reasons NYT headlines look visually bolder than AP-style headlines. More words capitalized per line creates a denser, more emphatic appearance.
"Of" that opens or closes a title is always capitalized regardless of style. A title like "Of Mice and Men" capitalizes "Of" because it is the first word, not because of any preposition rule.
"Of" is two letters long and functions almost exclusively as a preposition. AP Style, Chicago Style, MLA Style, and AMA Style all lowercase it consistently. The only mainstream style that capitalizes it in the middle of a title is NYT Style.