Hydrokinetic energy, a relatively new kind of renewable energy, can be generated from flowing water in rivers or oceans. Hydrokinetic turbines (HKTs) are a major system for hydrokinetic energy, and the reliability of the HKTs is critical for both their lifecycle cost and safety. The objective of this work is to apply advanced methodologies of reliability analysis and reliability-based design to the transmission shaft design for a horizontal-axis, non-submerged HKT. The deterministic shaft design is performed first by considering failure modes of strength and deflection using distortion energy, maximum shear and deflection theories. Then the reliability analysis of the shaft designed is performed by using Sampling Approach to Extreme Values of Stochastic Process method (SAEVSP). Finally reliability-based design is applied to the transmission shaft design, which results in the minimal shaft diameter that satisfies the reliability requirement for a given period of operation time. Since the time-dependent river velocity process is involved, the time-dependent reliability method is used in the reliability-based design. The methodology for the shaft design in this work can be extended to the design of other components in the HKT system.