Establishing bioequivalence (BE) for immediate-release (IR) locally acting gastrointestinal (LAGI) drug products is challenging for the following reasons: these products reach the site of action before entering systemic circulation; many have minimal systemic absorption that traditional in vivo BE studies with pharmacokinetics (PK) endpoints may not be feasible; and comparative clinical endpoint (CCEP) BE studies are generally insensitive to detect formulation differences and require a large sample size. Therefore, alternative approaches to establish BE for such products are warranted. Solubility and dissolution may predict in vivo performance and serve as a surrogate for in vivo BE assessment. The current research is to investigate the impact of solubility and dissolution on BE recommendations in FDA’s published product-specific guidances (PSGs) for IR LAGI drugs. We collected data of solubility and dissolution in multiple pH media, and systemic absorption for 15 drug substances among 19 IR LAGI products to cover a variety of dosage forms including tablet, chewable tablet, capsule, suspension, and powder from new drug applications and abbreviated new drug applications. The corresponding BE recommendations in the total of 19 PSGs regarding qualitative (Q1) and quantitative (Q2) formulation, in vitro comparative dissolution testing, BE studies with PK or clinical endpoints were also collected for each product. Based upon the in vivo absorption profiles, the 19 drug products were divided into the systemically detectable group for 11 products and the systemically undetectable group with approximately zero absorption for eight products. In the systemically undetectable group, six out of seven drug substances exhibit high solubility, as according to the Biopharmaceutics Classification System criteria, while in the systemically detectable group, only one out of eight drug substances has high solubility. For all seven highly soluble drugs, in vitro multi-media dissolution testing is recommended in the PSGs if Q1/Q2 sameness products, while for non-Q1/Q2 sameness products, additional BE studies with PK or clinical endpoints are recommended, except that for one product (magnesium sulfate; potassium chloride; sodium sulfate tablets) where only one medium dissolution testing is recommended. For the 12 drug products (two systemically undetectable and 10 systemically detectable) containing the low soluble drug substances, the PSGs recommend additional in vitro BE studies (i.e., binding), in vivo BE studies with PK endpoints for Q1/Q2 sameness formulations, and additional CCEP BE studies for non-Q1/Q2 sameness formulations. The solubility of drug substance was found as a critical physiochemical characteristic for in vitro and in vivo performance for IR LAGI drug products. As a result, for IR LAGI drug products with high solubility for Q1/Q2 sameness formulation, an in vitro multi-media or one medium dissolution testing may be sufficient to establish BE. However, for low soluble drugs, in vitro and in vivo performance were found to be less predictable based on in vitro data alone. Thus, additional in vivo BE studies with PK and/or clinical endpoints should be recommended based on either Q1/Q2 or non-Q1/Q2 sameness formulations, in addition to in vitro multi-media dissolution testing. The science-based BE recommendations for IR LAGI drug products have facilitated the development of generic drug products, promoted affordable, high quality and safe medicines available to American public, and benefitted public health.