The magazine's original goal was to write about and publish programs for all of the computers that used some version of the MOS Technology 6502 CPU. It started out with the Commodore PET, Commodore VIC-20, the Atari 8-bit series, the Apple II plus, and some 6502-based computers one could build from kits, such as the Rockwell AIM 65, the KIM-1 by MOS Technology, and others from companies such as Ohio Scientific. Support for the kit computers and the Commodore PET were eventually dropped. The platforms that became mainstays at the magazine were the Commodore VIC-20, Commodore 64, Atari 8-bit series, TI-99/4A, and the Apple II series. Later on the 6502 platform focus was dropped and IBM PC, Atari ST series, and the Commodore Amiga series computers were added to its line-up. Compute! also published a very successful line of computer books, many of which consisted of compilations of articles from the magazine.

Most personal computers of the time came with some version of the BASIC programming language. The magazine often featured type-in programs written in these versions of BASIC for their respective computers. Machine code programs were also published, usually for simple video games listed in BASIC DATA statements as hexadecimal numbers that could be POKEd into the memory of a home computer by a 'stub' loader at the beginning of the program. Machine language listings could be entered with a program provided in each issue called MLX (available for Apple II and Commodore hardware, and written in BASIC). Early versions of MLX accepted input in decimal, but this was later changed to the more compact hexadecimal format. It was noted particularly for software such as the multiplatform word processor SpeedScript, the spreadsheet SpeedCalc, and the game Laser Chess.

Editors of the magazine included Robert Lock, Richard Mansfield, Charles Brannon, and Tom R. Halfhill. Noted columnists included Jim Butterfield, educator Fred D'ignazio and science fiction author Orson Scott Card.[2] In May 1988, the magazine changed its focus to PCs and PC clones and dispensed with the type-in listings. During the early 1990s, with the decline of the home computer market in favor of the PC market, Compute! went out of publication for a while until it was sold to General Media, publishers at the time of Omni and Penthouse magazines. Ziff Davis bought Compute!'s assets, including its subscriber list, in 1994. General Media had ceased its publication before the sale.

Descriptions of the various issues have come from Kevin Savetz, Ian Cogill, Andrew Stephen and Jason Scott.