(1) Exoskeletons offer potential benefits for overhead working tasks, but gender effects or differences are unclear. This study aimed to compare the performance as well as subjective body strain and comfort of men and women using an upper-body exoskeleton. (2) n = 20 female and n = 16 male participants performed an overhead drilling task with and without a passive upper-body exoskeleton in a randomized cross-over study. The task performance of different movement phases, perceived exertion, and ease of use were measured to compare gender differences. One- and two-way analyses were used to compare genders in the different conditions. The body mass index (BMI) was included as a covariate. (3) Gender differences in task performance were found for error integrals (p < 0.001) with higher values in male participants. Moreover, there was a significant interaction effect for gender x exoskeleton use. While females showed performance decrements in aiming with exoskeleton use, the males’ performance increased (p = 0.025). No other gender differences were observed. (4) Gender differences in task performance using an upper-body industrial exoskeleton were less detectable than expected, indicating that body composition and anthropometrics might be valuable indicators for performance including assisting devices. Moreover, future studies should also integrate the examination of muscle activity to gain more insights into potential gender movement control patterns.