The majority of innovative drug candidates are poorly water soluble and exhibit basic properties. This makes them highly dependent on the in vivo encountered acid–neutral pH sequence to achieve a sufficient dissolution and thus absorption. In this study, we evaluated the pH-independent generation of intraluminally induced supersaturation of the model compound itraconazole and its beneficial effect on the extent of absorption in the Caco-2 system and the rat in situ perfusion system. Local supersaturation was obtained by means of a solvent shift method and a novel formulation strategy based on ordered mesoporous silica (OMS) as a carrier. In vitro results evidenced that both methods were capable of creating a supersaturated state of itraconazole in fasted state simulated intestinal fluid (FaSSIF) when no preceding acidic dissolution was simulated. The extent of supersaturation exceeded 21.9 and 9.6 during at least 4 h for the solvent shift method and OMS as a carrier, respectively. As compared to saturation conditions (0.09 ± 0.01 μg), supersaturation induced by the solvent shift method as well as by the use of OMS increased transport across a Caco-2 cell monolayer more than 16-fold, resulting in the basolateral appearance of 2.20 ± 0.29 μg and 1.46 ± 0.03 μg itraconazole after 90 min, respectively. In the absence of an acid–neutral pH sequence, the performance of the marketed product Sporanox® was inferior with total transport amounting to 0.12 ± 0.03 μg after 90 min. Enhanced absorption was confirmed in the in situ perfusion model where OMS was able to boost total transport of itraconazole after 60 min from 0.03 ± 0.01 nmol cm−1 to 0.70 ± 0.09 nmol cm−1 compared to saturated equilibrium conditions in FaSSIF. The solid dosage form Sporanox® again failed to achieve a similar extent of absorption enhancement (0.29 ± 0.01 nmol cm−1). These findings suggest that intraluminal supersaturation can be created by the use of OMS and that preceding dissolution of basic compounds in the acidic medium of the stomach is not required to allow for efficient intestinal absorption. The use of OMS appears to be a promising strategy for the delivery of especially basic low solubility compounds in patients suffering from hypochlorhydria; the pH independency may also result in a more reproducible systemic exposure.