Angiotensinogen (AGT) is the precursor of angiotensin II, a potent vasopressor in the renin-angiotensin-aldosterone system. Small interfering RNAs (siRNAs) targeting hepatic AGT can lower blood pressure in hypertension patients by reducing AGT levels, with effects lasting over 6 months. Existing siRNA molecules are effective, but novel ones with better inhibitory activity and longer duration periods may be developed. In this study, we demonstrated an entire development process for a novel siRNA targeting hepatic AGT. Through the proper combination of bioinformatic on-target/off-target screening on sequences, chemical modification patterns optimization, and liver-targeting delivery ligands conjugation, we have successfully developed several promising siRNAs with equivalent or better inhibitory activity, duration of effect, and safety profile compared with previously reported siRNA. Moreover, our comprehensive analysis has elucidated the correlation between the efficacy and free energy of siRNAs. Currently, there exists no reliable model capable of precisely predicting the activity and off-target risk associated with fully modified siRNAs. Therefore, the implementation of efficient screening procedures is of utmost importance during the development of siRNA candidates. This study presents a meticulous and valuable reference for the development of potent and safe siRNAs on other targets.