This study presents a detailed quantification of how flow orientation affects mass transfer and frictional resistance in periodically confined channels, offering novel insights into the physical similarity relations governing these phenomena. We constitute that the Sherwood number and friction factor adhere to universal scaling laws of the form Sh = A1+B sin(2α) Re1 2 and f = A1+B sin(2α) Re−1 2 , where α depicts the orientation of the periodically confined channel. It is found that the flow orientation and the cross flow velocity independently affect both, the Sherwood number and the friction factor. A key contribution of this work is the explicit characterization of the flow orientation: a 45° rotation of the flow relative to the spacer structure increases the Sherwood number by nearly 25%, while the friction factor rises by approximately 20%. These findings highlight a fundamental trade-off between mass transfer enhancement and flow resistance, suggesting that any process optimization must carefully balance the gains in mixing efficiency against the increased energy dissipation. This study provides a robust framework for further investigations into how periodic geometrical constraints influence transport processes in complex flow systems.