The road distance between Manhattan, Kansas and San Antonio, Texas is approximately 800 miles (1,287 kilometers) via the most direct interstate route.
Take I-35 South from Manhattan through Emporia, Wichita, and into Oklahoma (passing Oklahoma City), then continue through Dallas/Fort Worth, Waco, and Austin to San Antonio. This is a straight-shot, high-speed interstate the entire way.
Expect 11.5 to 12.5 hours of driving time under normal conditions. Add 1–2 hours for fuel/food/rest stops. Real-world door-to-door travel typically runs 13–14 hours.
US-281 South from Great Bend through Pratt, Medicine Lodge, into Texas via US-281/US-183 offers a more scenic, less congested "backbone of America" drive through the Flint Hills and Hill Country—but adds ~30 miles and 30–60 minutes.