The electrocatalytic conversion of CO2 waste into liquid fuels is one of the most promising approaches to contribute to carbon neutrality and sustainable energy cycles. Designing and screening efficient electrocatalysts to simultaneously reduce the overpotential required for the CO2 reduction reaction (CO2RR), enhancing product selectivity and current density, still remains challenging. The high concentration of S vacancies in sulfides that can serve as active sites offers the possibility to address these challenges. Here, this study deciphers the positive roles of S vacancies in boosting the adsorption and activation of CO2 by modulating the local electronic structure through theoretical simulations on the In4SnS8 platform. The comparison experiments confirm that sulfides with a high concentration of intrinsic S vacancies are more competitive in selectivity and activity. Afterward, the post-processing heating desulfurization method is employed to create more abundant artificial S vacancies to further verify its effectiveness. The HCOOH Faradaic efficiency (FE) of the post-processed V-In4SnS8-350 with both intrinsic and artificial S vacancies is as high as 91%, which is much higher than 65% for pristine In4SnS8 with only intrinsic S vacancies. Meanwhile, the abundant artificial S vacancies not only upgrade the HCOOH yield from 2.2 to 14.0 mmol·h–1·cm–2 but also optimize the bias potential with the highest FE from −1.3 to −1.0 VRHE. These results highlight the effectiveness triggered by intrinsic and artificial S vacancies in enhancing the current density and lowering the optimal bias potential window, as well as improving the HCOOH selectivity. This work not only provides a sound guideline for the development of advanced sulfide semiconductor electrocatalysts but also renders insightful information on multifunctional S vacancies in the CO2RR.