Due to limited ultrasound detection angle, photoacoustic microscopy may own a relatively low sensitivity. To break this limit, we develop an ultra-sensitive optical resolution photoacoustic microscopy based on a customized acoustic lens with high numerical aperture (0.74) (HNA-OR-PAM). The sensitivity of HNA-OR-PAM is improved to around 160% as the state-of-the-art OR-PAM. It has the capability to measure oxygen saturation of mice’s ear in vivo with ~10nJ pulse energy, reducing the nonlinear effect induced by high pulse energy. In addition, photoacoustic signal of tilted objects could be enhanced due to augmented ultrasound detection angle, which has been validated in our phantom study and the brain imaging experiment in vivo.