The Colorado potato beetle (CPB) is the primary defoliator of potatoes and is notorious for its ability to develop resistance to various insecticides. This remarkable adaptability may partly reflect selective pressures imposed due to the beetle’s coevolution with toxic Solanaceous host plants. As the initial interface between the environment and the insect olfactory system, odorant-binding proteins (OBPs) may sequester excess harmful molecules, such as insecticides and plant allelochemicals, in the perireceptor space, mitigating deleterious effects on vulnerable olfactory sensory neuronal dendrites. In this study, we identified an antenna-specific OBP (LdecOBP33) that is significantly upregulated in a pesticide resistant strain compared to a susceptible one. Competitive displacement fluorescence binding assays demonstrated that the LdecOBP33 protein exhibited broad affinity toward a range of plant volatiles and insecticides. Silencing LdecOBP33 decreased the beetle’s resistance to imidacloprid and impaired its ability to locate host plants. Together, these findings provide insight into a key molecular factor involved in the CPB’s response to environmental challenges, suggesting a potential link between insects’ adaptation to xenobiotics and their olfactory processing.