We introduce a microfluidic approach to simulate tumor hypoxia and vascular anomaly. Polydimethylsiloxane (PDMS) phantoms with embedded microchannel networks were fabricated by a soft lithography process. A dialysis membrane was sandwiched between two PDMS slabs to simulate the controlled mass transport and oxygen metabolism. A tortuous microchannel network was fabricated to simulate tumor microvasculature. A dual-modal multispectral and laser speckle imaging system was used for oxygen and blood flow imaging in the tumor-simulating phantom. The imaging results were compared with those of the normal vasculature. Our experiments demonstrated the technical feasibility of simulating tumor hypoxia and vascular anomalies using the proposed PDMS phantom. Such a phantom fabrication technique may be potentially used to calibrate optical imaging devices, to study the mechanisms for tumor hypoxia and angiogenesis, and to optimize the drug delivery strategies.