Background: New wearable assistive devices (exoskeletons) have been developed for assisting people during work activity or rehabilitation. Although exoskeletons have been introduced into different occupational fields in an attempt to reduce the risk of work-related musculoskeletal disorders, the effectiveness of their use in workplaces still needs to be investigated. This systematic review focused on the effects of upper-body exoskeletons (UBEs) on human metabolic cost and thermophysiological response during upper-body work tasks. Methods: articles published until 22 September 2020 were selected from Scopus, Web of Science, and PubMed for eligibility and the potential risk of bias was assessed. Results: Nine articles resulted in being eligible for the metabolic aspects, and none for the thermal analysis. All the studies were based on comparisons between conditions with and without exoskeletons and considered a total of 94 participants (mainly males) performing tasks involving the trunk or overhead work, 7 back-support exoskeletons, and 1 upper-limb support exoskeleton. Eight studies found a significant reduction in the mean values of the metabolic or cardiorespiratory parameters considered and one found no differences. Conclusions: The reduction found represents a preliminary finding that needs to be confirmed in a wider range of conditions, especially in workplaces, where work tasks show different characteristics and durations compared to those simulated in the laboratory. Future developments should investigate the dependence of metabolic cost on specific UBE design approaches during tasks involving the trunk and the possible statistical correlation between the metabolic cost and the surface ElectroMyoGraphy (sEMG) parameters. Finally, it could be interesting to investigate the effect of exoskeletons on the human thermophysiological response.