Aloe vera gel (AVG) which is increasingly used as an excipient in sustained release pharmaceutical dosage forms due to its health benefits is sporadically studied as a drug carrier for controlled delivery. Guar-gum (GG) used for colon specific delivery is not a desirable matrix for the sustained release of 5-Fluorouracil (5-FU) in stomach and small intestine (SI) for treatment of stomach cancer as only 2% of 5-FU is released. Hence AVG is investigated as a co-carrier with GG to facilitate a sustained release of 5-FU in stomach in the present study. GG is solution blended with AVG in different proportions to achieve sustained release of 5-FU, in simulated biofluids. FT-IR, TG and DSC studies reveal only a mild physical interaction of the drug with the matrix through weak hydrogen bonding and there is no drug-matrix chemical interaction. The temperature of major weight loss degradation decrease both on the addition of drug and AVG. The in vitro release characteristics of the drug imply that addition of AVG to GG facilitate sustained release of 5-FU in stomach and SI due to enhanced matrix swellability. Blend composition and pH of the fluid control the release kinetics and the mechanism of release is found to be non-Fickian. The study demonstrates that AVG/GG blend of appropriate composition may serve as a promising matrix for the sustained release of 5-FU in stomach and SI which is difficult with pristine GG and AVG