Micro-electro-mechanical systems (MEMS) have been crucial in revolutionizing healthcare and environmental monitoring. By probing biological systems in mechanical, thermal, electrical and chemical modalities, one can gain a multiphysical characterization and understanding of the biological system. This understanding can be used for a more informed treatment of the disease. A key attribute for the success of MEMS biosensors and surgical tools is their ability to measure biological quantities and gather multimodal information with high resolution while minimizing their invasiveness for chronic reliability. In this dissertation, four areas are explored where strategies have been developed to minimize biosensor invasiveness and multimodal tissue characterization. Ultrasonic horn neural probes driven at their longitudinal resonance can allow penetration through tissue with less force and induce less tissue damage. A model governing the force reduction proportions to ultrasonic horn probes on driving voltage, insertion velocity, and substrate elasticity is presented to guide design and use of ultrasonic horn probes in neural interface application. An animal model is developed for monitoring probe-tissue interaction over time using two-photon microscopy both electrically and optically. Secondly, a detachable ultrasonic neural probe inserter is developed. Multiple neural probe geometries and configurations are affixed to the ultrasonic inserter using the polyethylene glycol polymers as an adhesive and a biodissolvable material. Neural probes can be bonded and debonded reversibly to a silicon inserter with reduced implantation forces. This insertion method can potentially help inserting neural probes made in many different microfabrication technologies. Thirdly, a silicon tweezer is presented. The silicon structure that can perform tweezing motion without silicon fracture is demonstrated. The silicon tweezer can be used for measuring multiple tissue electromechanical properties including the tissue Young's modulus, tissue penetration force, and electrical impedance. This tweezer can potentially provide more tissue information for surgeons deciding on several options to suture, or remove tissue. Finally, an ultrasonically actuated silicon probe viscometer with integrated immersion depth sensors and strain gauges were demonstrated. The immersion depth and viscosity information from the liquid can be measured simultaneously. This can potentially solve a major problem of depth calibration in the portable applications of ultrasonic viscometers.