Organic and inorganic composite contamination is a critical barrier to the efficiency of membrane distillation (MD) processes. This study investigated the impacts of humic acid (HA), sodium chloride (NaCl), and calcium chloride (CaCl2) as representative organic and inorganic contaminants on MD performance. The findings indicated that Ca2+ caused more severe membrane clogging and irreversible fouling compared to Na+. To understand the interaction between HA and cations, the study utilized XDLVO theory and molecular dynamics simulations. The results demonstrated that Ca2+ instigated a bridging effect, leading to lower energy barriers and higher binding energies, thereby enhancing HA adsorption onto the membrane. Conversely, Na+ facilitated an electrostatic shielding effect, which resulted in reduced particle size and facilitating agglomeration around HA molecules. In the HA–Na+–Ca2+ system, a clear interplay and competition between Na+ and Ca2+ were observed. The aggregation effect of Na+ hindered the bridging between HA and Ca2+, leading to NaCl crystal precipitation. Overall, this research provided valuable insights into the fouling mechanisms within MD caused by organic-inorganic composite contaminants.