In this contribution, we present a chemically efficient and sustainable protocol for the palladium-catalyzed copper-free Sonogashira cross-coupling reaction, based on the use of a heterogeneous catalytic system. This consists in the combination of a palladium catalyst on highly cross-linked thiazolidine network on silica and a polystyrene-supported base. The solid catalyst/base system acts as a palladium scavenger avoiding leaching of the metal and consequent product contamination. The reaction can be conducted in safe and easily recoverable acetonitrile/water azeotrope as reaction medium. This proved to be an efficient greener alternative to the classic toxic aprotic media commonly used in cross-coupling reaction, such as DMF and NMP. Acetonitrile/water azeotrope could be easily recovered and reused allowing the minimization of waste production. Our approach, based on the use of both a supported base and a supported catalyst, has proven to be efficient for the waste reduction, as proved by the low E-factor values achieved.