This paper proposes a robust design-optimization approach for eBike drive units that incorporates the highly variable driver-dependent load collectives and system conditions into a fatigue calculation. In an initial step, the relevant influences and loads on the investigated system are examined and reviewed in relation to the current normative requirements. From a methodical viewpoint, this paper presents a surrogate-based simulation-based approach to assess reliability across the entire geometry according to a probabilistic fatigue calculation. The probabilistic evaluation considers the several measured load collectives of different drivers and driving scenarios to enable a robust and type-oriented bike design. In addition to methods of fatigue calculation, this approach also includes common methods of order reduction and reliability-based design optimization. To avoid additional uncertainties in the calculation, this approach considers a complex critical-plane-based multiaxial-fatigue calculation to correctly evaluate the multiaxial and non-proportional stress state across the whole geometry. A data-based surrogate model that supports the fatigue calculation by predicting the load across the given uncertainties is the key to the efficient assessment of the service life of the eBike. Lastly, the identified uncertainties in the design of eBike drive units are investigated and evaluated by this method.