The receptor recognition and interaction of plasma lipoproteins (e.g., native low-density lipoproteins (LDL)/oxidized low-density lipoproteins (oxLDL), as well as the influence of microenvironmental/lysosomal acidification, play critical roles in lipoprotein metabolism and diseases (e.g., atherosclerosis) but have been less investigated. Here, the recognition/interaction of LDL or oxLDL with LDL receptor (LDLR) or CD36 (a scavenger receptor) or with living cells at various pHs was evaluated mainly via atomic force microscopy (AFM). To improve force measurement accuracy, a novel, micro-droplet-based method for AFM probe functionalization was developed. We found that solution acidification significantly reduced the LDL-LDLR binding at pH ≤ 6.4, whereas the oxLDL-CD36 binding had no significant change until pH ≤ 4.4. Compared with a traditional immersion method, our micro-droplet method for AFM probe functionalization produced more accurate interaction forces, and revealed that acidification significantly reduced the LDL-LDLR/cell interaction forces, instead of the oxLDL-CD36/cell-specific interaction forces and nonspecific interaction forces. The data imply that the LDL-LDLR/cell recognition and interaction are susceptible to acidification, whereas the oxLDL-CD36/cell recognition and interaction are tolerant of acidification. The results may provide important novel information and biomechanical/pathological implications for understanding lipoprotein metabolism and atherosclerosis.