As demand for clean water rises, water reuse has become an important strategy. Reclaimed water (RW), treated residential and municipal wastewater, has emerged as a potential solution for irrigation, industrial applications, and groundwater recharge. Despite these potential benefits, RW can contain elevated levels of contaminants such as nutrients, heavy metals, pharmaceuticals, and microplastics, which pose environmental risks when discharged into aquatic ecosystems. Wastewater treatment plants often incorporate constructed wetlands (CWs) to treat RW by mimicking natural wetland functions (i.e., microbial activity, plant uptake, and soil remediation). However, there is limited understanding of how the chemical signatures of CWs differ from natural wetlands, and how these signatures vary across different CW designs (single vs. hybrid connected systems). Our study addresses this gap by quantifying chemical signatures of natural and engineered wetlands and identifying the chemical parameters driving these variations. We hypothesize that (1) CWs differ chemically from natural wetlands, and (2) Hybrid CWs more closely resemble natural wetlands than single CWs, with downstream cells in hybrid systems exhibiting more natural chemical signatures. To test these hypotheses, we sampled 7 natural wetlands, 6 single CWs, and 1 hybrid CW system with 9 wetland cells spanning four treatment stages during the wet season across north-central Florida, USA. At each site, we measured in situ physical parameters (temperature, DO, pH, and conductivity) and collected water samples to characterize various forms of nitrogen, phosphorus, and carbon. Multivariate analyses revealed clear differentiation in chemical signatures between natural wetlands and CWs. CWs were associated with higher nitrogen, phosphorus, and conductivity, while natural wetlands showed higher dissolved oxygen and temperature. Chemical signatures also varied among CW designs. In hybrid systems, chemical signatures shifted progressively as RW moved through treatment stages, with downstream cells exhibiting lower nutrient concentrations and distinct physical characteristics. Our findings suggest that engineered wetlands differ chemically from natural wetlands, and that CW design and management influence their chemical signatures. Our research has the potential to improve the design and implementation of CWs for RW treatment, reducing environmental risks, which is particularly important as RW is increasingly used worldwide to support water conservation efforts.