High-throughput screening methods have increased the number of poorly water-soluble, highly permeable drug candidates. Many of these candidates have increased bioavailability when administered with food (i.e., exhibit a positive food effect). Food is known to impact drug bioavailability through a variety of mechanisms, including drug solubilization and prolonged gastric residence time. In vitro dissolution media that aim to mimic in vivo gastrointestinal (GI) conditions have been developed to lessen the need for fed human bioequivalence studies. The objective of this work was to develop an in vitro lipolysis model to predict positive food effect of three BCS Class II drugs (i.e., danazol, amiodarone and ivermectin) in previously developed lipolysis media. This in vitro lipolysis model was comparatively benchmarked against FeSSIF and FaSSIF media that were modified for an in vitro lipolysis approach, as FeSSIF and FaSSIF are widely used in in vitro dissolution studies. The in vitro lipolysis model accurately predicted the in vivo positive food effect for three model BCS class II drugs. The in vitro lipolysis model has potential use as a screening test of drug candidates in early development to assess positive food effect.