People who use the thumb in repetitive manipulation tasks are likely to develop thumb related impairments from excessive loading at the base joints of the thumb. Biologically informed wearable robotic assistive mechanisms can provide viable solutions to prevent occurring such injuries. This paper tests the hypothesis that an external assistive force at the metacarpophalangeal joint will be most effective when applied perpendicular to the palm folding axis in terms of maximizing the contribution at the thumb-tip as well as minimizing the projections on the vulnerable base joints of the thumb. Experiments conducted using human subjects validated the predictions made by a simplified kinematic model of the thumb that includes a foldable palm, showing that: (1) the palm folding angle varies from 71. 5 ∘ to 75. 3 ∘ (from the radial axis in the coronal plane) for the four thumb-finger pairs and (2) the most effective assistive force direction (from the ulnar axis in the coronal plane) at the MCP joint is in the range 0 ∘< ψ< 30 ∘ for the four thumb-finger pairs. These findings provide design guidelines for hand assistive mechanisms to maximize the efficacy of thumb external assistance.