Unless you want the long, scenic route, either of your choices (80 or 54) will take you past Guadalajara via the southern section of the 'periferico'.
You will see good signs for Mexico and should follow them to the Autopista. It will split around 20 Km east of Guadalajara and you will want to follow the signs for Lagos de Moreno, etc. which will keep you on 80 to San Luis Potosi and then, northward to Matehuala.