Artificially-tilted multilayer transverse thermoelectric devices (ATMTTDs) have a large degree of design freedom, which is convenient for designing devices for different working conditions. However, evaluation and preparation of ATMTTDs has generally been based on trial and error, and coherent performance optimization strategies for different ATMTTDs applications is still lacking. Here, the relationship between performance evaluation indicators, transverse thermoelectric properties, and geometric structure parameters of ATMTTDs has been established via theoretical calculation and experimental verification. The results show that the tilt angle (θ) has a key effect on the transverse thermoelectric properties of ATMTTDs. The optimal transverse thermoelectric figure of merit, power factor, and Seebeck coefficient of Ni/Bi0.5Sb1.5Te3 (BST) ATMTTDs are theoretically predicted at tilt angles of 11°, 21°, and 45°, respectively. Ni/BST ATMTTDs have been fabricated and the experimental results demonstrated that a maximum power generation efficiency of 1.01% and maximum effective refrigeration temperature difference of 0.4 K are reached at θ = 11°, maximum output power density of 411 W/m2 is obtained at θ = 21°, and a maximum response sensitivity of 420 μV/K is achieved at θ = 45°, which is in good agreement with theoretical predictions. This work provides theoretical guidance for manufacturing ATMTTDs for different applications.