The discovery of Sn(II)-containing oxide semiconductors has been severely limited by a lack of understanding of the factors leading to their thermodynamic stability, e.g., chemical compositions and structure types, as well as by the absence of productive synthetic routes. The relatively few reported Sn(II)–O–M (M = early transition-metal cation) semiconductors frequently decompose at moderate to low temperatures. Herein, a large-scale predictive modeling approach was used to assess the structural factors yielding their enhanced thermodynamic stability. This has resulted in 10 new predicted Sn(II)-containing oxides that are proposed to fall within reasonable synthetic limits. Increasing stability was found for structures possessing lower Sn(II)/M ratios and local asymmetric coordination environments allowing the expression of the Sn(II) stereoactive lone pair. As a test of these results, synthetic efforts to prepare one of the proposed compounds starting from BaLa4Ti4O15 yielded the predicted layered-perovskite SnLa4Ti4O15 (SLTO). The new SLTO crystallizes in the noncentrosymmetric and polar P3c1 space group (no. 158) as confirmed by Rietveld refinements of powder X-ray diffraction (XRD) data and second harmonic generation activity. Full Sn(II) substitution was confirmed by a combination of XRD structural refinements, 119Sn Mössbauer spectroscopy, SEM-EDS, and X-ray photoelectron spectroscopy. UV–vis diffuse reflectance data confirmed that SLTO has a visible-light absorbing band gap of ∼2.4 eV and is a promising photocatalyst for solar energy conversion. After loading its surfaces with a Rh/Cr2O3–CoOx dual-cocatalyst, SLTO with hexagonal plate-shaped morphologies showed activity for overall water splitting at a rate of ∼317 μmol g–1 h–1 H2 and an apparent quantum yield of ∼22%. Thus, these results highlight the synergistic combination of chemical intuition, predictive modeling, and synthetic design in the synthesis of new Sn(II)-containing semiconductors for promising applications of their optical properties and photocatalytic activities for water splitting.