The bilayer tablet contains two layers of materials. However, such tablets have higher tendency to crack at the interface or even layer separation. Interfacial bonding strength (IBS) is the strength that bonds two layers at the interface. Understanding the mechanism of forming an adequate IBS is critical to the successful development of a bilayer tablet product. The first step is to establish a standard measuring method for obtaining accurate IBS. Both shear and tensile tests are commonly used to measure IBS, which shows a linear correlation. However, the shear test has a more complicated result due to complex stress application and tablet testing orientation, which is not an issue for the tensile test. Therefore, the tensile test is preferred for straightforward data interpretation because of uniform applied stress. Thus, the tensile strength becomes a standard method for measuring IBS. IBS of four layer combinations between microcrystalline cellulose (MCC) and lactose 24AN (Lac), i.e., MCC/MCC, Lac/Lac, MCC/Lac and Lac/MCC (1st/2nd), were measured under various first layer (P1) and second layer compaction pressures (P2) to validate the hypothesis that IBS is controlled by bonding area (BA) and bonding strength (BS) interplay at the interface. BA is the contact area between first layer and second layer powders at the interface and BS is the strength interactions over the contact area. As a result, any factors that influence either BA or BS affect IBS. Moreover, differential radial expansion between layers also affects IBS. In this work, BA is assessed by surface waviness and tablet porosity, while BS is assessed by tablet strength at zero porosity. Lower P1 leads to higher porosity of the first layer and higher P2 generally leads to greater surface waviness at the interface, both leading to larger BA and, thus, higher IBS. However, higher P2 causes a larger difference in radial expansion when two layers are different materials, which weakens IBS. The materials in the two layers determine BS, which follows the descending order of MCC/MCC > MCC/Lac (Lac/MCC) > Lac/Lac. The trends in the effects of these factors on measured IBS support the hypothesis. Further, bilayer tablets with each layer containing the mixture of MCC and lactose in different ratios with/without hydroxypropyl methylcellulose (HPMC) K15M are studied to understand the compositional effect on IBS under two P1s (20 and 100 MPa) and a fixed P2 of 200 MPa. The multi-component bilayer tablets make the trend of IBS more complicated as a function of MCC content. Still, IBS changes can be explained by the BA and BS interplay. The increase of MCC can increase BS but, at the same time, decrease BA. The addition of HPMC decreases BS for lower IBS. The interplay between BA and BS will determine IBS. Particle size is also an important factor to affect IBS. Two sizes of microcrystalline cellulose (MCC) and lactose anhydrate were prepared to study the effect of particle size on IBS of bilayer tablets. The effect of particle size on IBS is also influenced by material mechanical properties. The results show lactose has an advantage as the first layer over MCC. With lactose in the first layer, IBS is generally higher and insensitive to particle size and materials in the second layer. However, MCC is a better fit in the second layer due to less sensitivity to particle size and materials in the first layer. The dependence of IBS on materials and particle size could be explained by the BABS interplay. The second layer prefers larger particles for higher BA but the first layer shows no preference in particle size. Besides, BS and radial expansion also influence the IBS, which necessitate being considered together between different layer combinations. IBS alone cannot stand to judge whether or not a bilayer tablet was strong enough to sustain the downstream manufacturing processes. A survival test using tablet friabilator is developed to determine the minimum interfacial bonding strength (IBSm) of bilayer tablets. From the result, IBSm depends on both layer compositions and tablet size. When bilayer tablets made with more brittle materials or larger tablet sizes, a higher IBSm was needed to pass the survival test. On the other hand, when a polymer, i.e. HPMC, was added, smaller IBSm still passed the survival test. Considering all the composition and tablet size, an IBSm of 0.26 MPa should be sufficient to avoid failure in bilayer tablet manufacturing in this work.