The low frequency of large destructive earthquakes in the Eastern Betics (SE Iberian Peninsula), not recorded in the instrumental seismic catalog, complicate the estimation of the maximum ground motion that could be reached. Knowing the characteristics and behavior of these large seismic ruptures is crucial for the study of seismic hazard. In this work, we have used a physics-based earthquake simulator to generate a 100 kyr catalog of seismic ruptures associated with seismogenic faults bordering the quaternary Guadalentin and Bajo Segura basins. From these ruptures, we have selected maximum earthquake scenarios, and those associated with certain probabilities of exceeding a severe magnitude from the synthetic catalog. The estimation of maximum peak accelerations (PGA) by means of ground motion prediction equations include a possible site amplification that we have calculated from a detailed geotechnical classification of soils. According to the simulations, the modeled faults have the capacity to generate maximum earthquakes with magnitudes ranging MW 6.7–7.4. Densely populated urban areas located along the Guadalentin valley, such as Lorca, could be subject to site-dependent PGA values close to 0.6 g on the Alhama de Murcia fault trace. Similar ground motion would affect the coastline of SE Alicante province when evaluating the maximum simulated event in the Bajo Segura offshore fault. But already from magnitudes around MW ∼ 6, PGA estimations exceed critical values of 0.5 g at the south side of the Bajo Segura basin and the city of Murcia, highly dependent of ground-motion amplification induced by thick deposits of very soft and saturated soils. Our scenarios reflect that other factors such as fault geometry, kinematics and the capability observed in the simulations to generate multi-fault ruptures also affect the spatial distribution of maximum ground motion in this region. We expect that this evaluation could contribute as an improvement guideline for future strong motion prediction studies prior to the settlement of new urban infrastructures in the Eastern Betics.