Mid-infrared (mid-IR) nonlinear optical (NLO) crystals are indispensable for the mid-IR lasers generation with tunable wavelengths from 3 to 20 µm. AgGaSe2 is a commercial mid-IR NLO crystal with the highest figures of merit, but suffers low laser damage threshold (LDT). To achieve the balance of optical transmission, NLO effect, and LDT, it is proposed to molecularly modify the AgGaSe2 structure by introducing the [LiSe4] tetrahedra, and successfully grow large crystals of a new selenide AgLiGa2Se4. The replacement of half of the heavy Ag+ cations with light Li+ increases the band gap to 2.2 eV (vs. 1.7 eV in AgGaSe2). The LDT value in AgLiGa2Se4 increases five times compared to that in AgGaSe2, while keeping a relatively large NLO susceptibility of 26 pm V−1. Moreover, the thermal expansion coefficients in AgLiGa2Se4 are approximately two times lower in absolute value compared with AgGaSe2, which is beneficial to the large crystal growth. All these advantages would make AgLiGa2Se4 a new promising NLO crystal for mid-IR laser applications.