The processes of particle–particle collision, adhesion, and detachment are omnipresent in the solid particle separation and purification processes. Nanobubbles, serving as a critical medium for interactions between particles, play a pivotal role in numerous fields of separation and purification such as mineral flotation, hydrometallurgy, chemical engineering, materials, and more. The elucidation of the principles governing nanobubbles’ involvement in interparticle interactions holds significant implications for enhancing and controlling separation and purification processes. The impact of nanobubbles on interparticle interactions between calcite particles was investigated in this study by measuring the forces between particles with and without nanobubbles and analysing them using DLVO and EDLVO theories. The experimental results demonstrate the occurrence of long-range attractive forces and significant adhesion between particles in the presence of nanobubbles under natural pH and ultrapure water conditions, phenomena that cannot be explained by classical DLVO theory. The generation of long-range hydrophobic attraction at the particle interface due to nanobubbles was confirmed through further EDLVO calculations and modifications, enhancing the stability of particle flocculation. Additionally, for the first time, the entire process from contact to detachment between the “particle-nanobubble” system in atomic force microscopy (AFM) simulations was described by combining experimental force curves with stepwise graphical interpretation. This approach provides valuable guidance for the analysis of bubble and soft matter interactions under AFM. The results of this study indicate that nanobubbles can indirectly alter the hydrophilicity and hydrophobicity of particles, increasing the probability of particle adhesion and reducing the probability of desorption, thereby enhancing the stability of particle flocculation.