The purpose of this study was to compare the powder properties, solubility, dissolution and oral absorption of solvent–wetted (SWSD) and kneaded (KNSD) l-sulpiride–loaded solid dispersions. The SWSD and KNSD were prepared with silicon dioxide, sodium laurylsulfate and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) using a spray dryer and high shear mixer, respectively. Their powder properties, solubility, dissolution and oral absorption were assessed compared to l-sulpiride powder. The drug in SWSD was in the amorphous state; however, in KNSD, it existed in the crystalline state. The SWSD with a drug/sodium laurylsulphate/TPGS/silicon dioxide ratio of 5/1/2/12 gave the higher drug solubility and dissolution compared to the KNSD with the same composition. The oral absorption of drug in the SWSD was 1.4 fold higher than the KNSD and 3.0 fold higher than the l-sulpiride powder (p < 0.05) owing to better solubility and reduced crystallinity. Furthermore, the SWSD at the half dose was bioequivalent of commercial l-sulpiride–loaded product in rats. Thus, the SWSD with more improved oral absorption would be recommended as an alternative for the l-sulpiride–loaded oral administration.