DNA strand displacement is widely used in DNA nanotechnology for programming functional DNA circuits. However, many of these systems depend on a single-stranded DNA overhang (toehold). Despite its popularity, eliminating the reliance on a toehold will advance the functionality and practicality of DNA circuits. Herein we develop a toehold-independent DNA strand displacement (TISD) reaction network for DNA logic circuits. Instead of leveraging enthalpic energy provided by the toehold, the TISD reaction employs configurational entropy as the driving force. The working principle, design framework, and practical functionality of the TISD were investigated. TISD-based DNA logic circuits show desirable performances on basic functions like cascaded, fan-in, and fan-out signal transduction. They also exhibit comparable performance on digital computing, including Boolean logic gates, multilayer circuits, and square root computation. As a promising alternative to canonical toehold-dependent systems, TISD will largely expand the design space of DNA-based molecular programming and inspire more versatile DNA-based functional systems.