Tylosin, an antibiotic used for maintaining livestock health, is a macrolide structurally similar to a number of important, often prescribed human antibiotics. Because of this relationship, tylosin presents a potential threat of antimicrobial resistance from environmental buildup. This work investigated tylosin sorption to natural diatomaceous earth product (DE) and the types of physical interactions responsible for sorption. Most sorption processes were best described by the Langmuir model when compared with Freundlich model. Heat of sorption (ΔH) was 1.14 kJ mol−1 indicating a physisorption process. Change in entropy (ΔS) was 119 J mol−1. Sorption was evaluated from aqueous solution with various H+, KCl and Urea concentrations. In 0.01 M phosphate buffer (PB) pH 6.6, a maximum sorption capacity of 15 mg tylosin per g of DE was achieved. Changing the pH to 2.9 or 11.2 resulted in decreased sorption of tylosin (13 and 10 mg g−1, respectively). Addition of 1 M KCl to 0.01 M PB pH 6.6 decreased sorption of tylosin to DE with the maximum binding capacity of 7 mg g−1. Sorption in 1.0 M urea, 0.01 M phosphate buffer pH 6.6 showed a maximum sorption of 13 mg g−1. Based on these results, the sorption of tylosin appears to be a physisorption process, with charge-charge interactions being the mode of sorption at neutral pH and small contributions from secondary interactions. This information will be useful for developing effective strategies for mitigating tylosin and other antimicrobial's impact on the environment. Display omitted •Tylosin physisorbed to diatomaceous earth with max loading of 18 mg/g.•Initial sorption event occurred rapidly followed by a much slower sorption event.•Highest sorption occurred at pH 6.6 compared to pH 2.9 and 11.2.•Salt and urea decreased sorption at concentrations above 0.01 M.•Sorption occurred by cationic and hydrophobic/hydrogen bonding interactions.