<p>Social behavior deficits are a hallmark of autism and other neuropsychiatric disorders. <i>SHANK3</i>, a common causal gene for autism, is highly expressed in the nucleus accumbens (NAc), a critical brain region for social behaviors. We previously characterized conventional <i>Shank3</i>^{<i>Δe4-22</i>} deletion mice with increased unilateral social investigation and hypoactive NAc circuits. Here, we describe a new exon 4-22 floxed (<i>Shank3</i>^{<i>flox/flox</i>}) mouse line that we developed to test the hypothesis that SHANK3 in the NAc is necessary for social behaviors. We find that knockdown of <i>Shank3</i> in the NAc of male and female mice decreases social preference in the 3-chamber assay and decreases social motivation in the social conditioned place preference assay. <i>Shank3</i> NAc deficiency does not alter food reward seeking, reciprocal social investigation, or anxiety-like behaviors, which we report in conventional <i>Shank3</i>^{<i>Δe4-22</i>} deletion mice. These data elucidate a specific mechanism of <i>Shank3</i> in the NAc on social behavior and social motivation.</p>