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Abstract Lyophilization is a common unit operation in pharmaceutical manufacturing but is a prolonged vacuum drying process with poor energy utilization. Microwave-assisted vacuum drying has been investigated to accelerate the lyophilization process. However, the literature lacks methodical approaches that consider the lyophilizer, the lyophilizate, the microwave power uniformity, the resulting heat uniformity, and the scalability. We present a microwave–vacuum drying method based on the statistical electromagnetics theory. The method offers an optimum frequency selection procedure that accounts for the lyophilizer and the lyophilizate. The 2.45 GHz frequency conventionally utilized is proven to be far from optimum. The method is applied in a microwave-assisted heating configuration to pharmaceutical excipients (sucrose and mannitol) and different myoglobin formulations in a lab-scale lyophilizer. At 18 GHz frequency and 60 W microwave power, the method shows nearly three times speed-up in the primary drying stage of sucrose relative to the conventional lyophilization cycle for typical laboratory batches. The uniformity of the microwave power inside the chamber is controlled within ± 1 dB. The resulting heating uniformity measured through residual moisture analysis shows 12.7% of normalized SD of moisture level across the batch in a microwave-assisted cycle as opposed to 15.3% in the conventional cycle. Conventional and microwave lyophilized formulations are characterized using solid-state hydrogen-deuterium exchange-mass spectrometry (ssHDX-MS), solid-state Fourier transform infrared spectroscopy (ssFTIR), circular dichroism (CD), and accelerated stability testing (AST). Characterization shows comparable protein structure and stability. Heat and mass transfer simulations quantify further effects of optimal volumetric heating via the high-frequency statistical microwave heating.