Membrane distillation (MD) has a great potential in desalination and wastewater treatment, but the application of MD is significantly restricted by membrane scaling. Membrane scaling may be affected by biopolymers and humic substances, which are ubiquitous in aqueous environment. However, the impact of natural organics, in particular biopolymers, on gypsum scaling in MD is seldom investigated. In this work, the impact of such organic compounds on gypsum scaling were evaluated with synthetic gypsum solutions as well as a real desalination brine. Model biopolymers (i.e. bovine serum albumin (BSA) and sodium alginate (SA)) and model humic substances (humic acids (HA)), were used to investigate the effect of organics, and two types of organics occurrence were considered, i.e., forming a layer on the MD membrane and dissolved in the feedwater. Results show that the organic fouling layer exhibited a very limited impact on gypsum scaling during MD. The dissolved organics in the feedwater generally postponed rather than accelerated gypsum scaling and membrane wetting, particularly for BSA and HA. SA was less efficient in restricting gypsum scaling due to its higher carboxyl content and the stronger interaction with Ca2+. The morphological characterization showed that the biopolymers in the feedwater were able to induce crystal deformation and agglomeration, forming irregular cluster-like crystals. Regarding the real desalination brine, the presence of BSA at 50 mg L–1 apparently delayed the occurrence of gypsum scaling from a concentration factor of 2.7–3.2. As a conclusion, the impact of natural organics on gypsum scaling should be considered in designing and operating MD for wastewater treatment.