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This paper presents a schematic-based and system-oriented modeling and simulation framework to enable top-down designs of multifunctional biofluidic lab-on-a-chip systems. An analog hardware description language (Verilog-A) is used to integrate parameterized and closed-form models of elements with different functionalities (e.g., mixing, reaction, injection and separation). Both DC and transient analysis are performed on a practical competitive immunoassay chip to capture the influence of topology, element sizes, material properties and operational parameters on the chip performance. Accuracy (relative error generally less than 5%) and speedup (>100×) of the schematic-based simulation is obtained by comparison to continuum numerical simulation as well as experimental measurements. A redesign of the original LoC device using our framework to improve bio-analysis efficiency and minimize chip-area has been demonstrated.