One of the ways natural and synthetic systems regulate temperature is via circulating fluids through vasculatures embedded within their bodies. Because of the flexibility and availability of proven fabrication techniques, vascular-based thermal regulation is attractive for thin microvascular systems. Although preliminary designs and experiments demonstrate the feasibility of thermal modulation by pushing fluid through embedded micro-vasculatures, one has yet to optimize the performance before translating the concept into real-world applications. It will be beneficial to know how two vital design variables—host material’s thermal conductivity and fluid’s heat capacity rate—affect a thermal regulation system’s performance, quantified in terms of the mean surface temperature. This paper fills the remarked inadequacy by performing adjoint-based sensitivity analysis and unravels a surprising non-monotonic trend. Increasing thermal conductivity can either increase or decrease the mean surface temperature; the increase happens if countercurrent heat exchange—transfer of heat from one segment of the vasculature to another—is significant. In contrast, increasing the heat capacity rate will invariably lower the mean surface temperature, for which we provide mathematical proof. The reported results (a) dispose of some misunderstandings in the literature, especially on the effect of the host material’s thermal conductivity, (b) reveal the role of countercurrent heat exchange in altering the effects of design variables, and (c) guide designers to realize efficient microvascular active-cooling systems. The analysis and findings will advance the field of thermal regulation both on theoretical and practical fronts.