This study aimed to evaluate the effect of hydrofluoric (HF)-acid-etching time and the impact of a resin-cement layer on the biaxial flexural strength and structural reliability of a zirconia-reinforced lithium silicate (ZLS) glass ceramic. Disc-shaped specimens (n = 15) were divided according to: etching time (conditioning with 10% HF acid for 20, 40, and 60 seconds), and application of a resin-cement layer. Biaxial flexural, contact angle, and roughness analyses were performed. When the resin-cement layer was not present, flexural strength data increased with increasing etching times: 20 seconds = 250.8 MPa; 40 seconds = 278.4 MPa; 60 seconds = 342.9 MPa. Application of resin cement increased the strength values (20 seconds of acid etching on specimens with a resin-cement layer = 341.8 MPa). Different etching times did not affect the roughness of ZLS, and the contact-angle analysis presented lower values for 60 seconds of acid etching. The flexural strength of ZLS was only sensitive to surface changes when less exposure time was conducted. Longer etching times (40 and 60 seconds) should be considered for conditioning ZLS ceramic along with adhesive cementation.