This study investigated the fatigue failure load of simplified monolithic yttria partially stabilized zirconia polycrystal restorations cemented to a dentin-like substrate using different luting systems. Disc-shaped ceramic (Zenostar T, 10 mm Ø × 0.7 mm thick) and dentin-like substrate (10 mm Ø × 2.8 mm thick) were produced and randomly allocated into eight groups, without or with thermocycling (TC=5–55°C/12,000×): “cement” (RelyX Luting 2 – glass ionomer cement [Ion], [Ion/TC]; RelyX U200 – self-adhesive resin cement [Self], [Self/TC]; Single Bond Universal+RelyX Ultimate – MDP-containing adhesive + resin cement [MDPAD + RC], [MDP-AD + RC/TC]; ED Primer II+Panavia F 2.0 – Primer + MDP-containing resin cement [PR + MDP-RC], [PR + MDP-RC/TC])). Each luting system was used as recommended by the manufacturer. Staircase methodology (20 Hz; 250,000 cycles) was applied for obtaining the fatigue failure loads. Fractographic characteristics were also assessed. At baseline, the Ion group presented the lowest fatigue load, although it was statistically similar to the Self group. The resin-based cement systems presented the highest fatigue performance, with the Ion group being only statistically equal to the Self group. Thermocycling influenced the groups differently. After aging, the MDP-AD + RC presented the highest mean, followed by the PR + MDP-RC and Self groups, while the Ion group had the lowest mean. Fractographic analysis depicted all failures as radial cracks starting at the zirconia intaglio surface. The luting system with MDP-containing adhesive applied prior to the resin cement presented the highest fatigue failure load after aging, presenting the best predictability of stable performance. Despite this, monolithic zirconia presents high load-bearing capability regardless of the luting agent.