The poor aqueous solubility of existing and emerging drugs is a major issue faced by the pharmaceutical industry. Water-miscible organic solvents, termed co-solvents, can be used to enhance the solubility of poorly soluble substances. Typically, drugs with poor aqueous solubility and Log P > 3 are not amenable to delivery across the skin. This study investigated the use of co-solvents as reservoirs to be used in combination with hydrogel-forming microneedles to enhance the transdermal delivery of hydrophobic compounds, namely Nile red, olanzapine and atorvastatin. A custom-made Franz cell apparatus was fabricated to test the suitability of a liquid drug reservoir in combination with polymeric microneedles. A co-solvency approach to reservoir formulation proved effective, with 83.30% ± 9.38% of Nile red dye, dissolved in 1 mL poly(ethylene glycol) (PEG 400), permeating neonatal porcine skin over 24 h. PEG 400 and propylene glycol were found to be suitable reservoir media for olanzapine and atorvastatin, with approximately 50% of each drug delivered after 24 h. This work provides crucial proof-of-concept evidence that the manipulation of microneedle reservoir properties is an effective method to facilitate microneedle-mediated delivery of hydrophobic compounds.