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Objective: Photoacoustics has been evolving rapidly in the recent several decades. With the aim of clinical translation, a photoacoustic imaging platform with a portable system size, a miniaturized imaging probe, and convenient handheld capability is of great demand. Methods: In this work, by adopting an ultrathin central-holed matrix array and a compact coaxial photoacoustic design, a water-free handheld photoacoustic imager is developed (weight: 44 g). Optical Monte Carlo simulation and acoustic k-wave simulation are performed to confirm a relatively homogenous photoacoustic sensitivity distribution within a wide field of view (larger than 10 × 10 × 10 mm3). Results: Imaging resolution characterized by imaging two hairs is estimated to be about 0.80 mm in the lateral direction and 0.73 mm in the axial direction. To demonstrate the handheld capability in real time, handheld imaging guided needle biopsy in the rat's abdomen is performed at a rate of about 10 Hz (CNR ∼ 14.3 dB). Furthermore, handheld imaging is also demonstrated on visualizing vasculature (mainly cephalic vein) in the human arm (CNR > 4.1 dB). Conclusion: Results demonstrate that the volumetric photoacoustic imaging system using a central-holed 2D matrix array is an attractive choice for achieving convenient handheld operation in real time. Significance: Such a compact handheld design may promote the clinical translation of photoacoustic technique. [ABSTRACT FROM AUTHOR]