<?xml version="1.0"?>
<ownershipDocument>

    <schemaVersion>X0206</schemaVersion>

    <documentType>3</documentType>

    <periodOfReport>2017-11-15</periodOfReport>

    <noSecuritiesOwned>1</noSecuritiesOwned>

    <issuer>
        <issuerCik>0001024126</issuerCik>
        <issuerName>PERNIX THERAPEUTICS HOLDINGS, INC.</issuerName>
        <issuerTradingSymbol>PTX</issuerTradingSymbol>
    </issuer>

    <reportingOwner>
        <reportingOwnerId>
            <rptOwnerCik>0001301047</rptOwnerCik>
            <rptOwnerName>Leone John R</rptOwnerName>
        </reportingOwnerId>
        <reportingOwnerAddress>
            <rptOwnerStreet1>C/O PERNIX THERAPEUTICS HOLDINGS, INC.</rptOwnerStreet1>
            <rptOwnerStreet2>10 NORTH PARK PLACE, SUITE 201</rptOwnerStreet2>
            <rptOwnerCity>MORRISTOWN</rptOwnerCity>
            <rptOwnerState>NJ</rptOwnerState>
            <rptOwnerZipCode>07960</rptOwnerZipCode>
            <rptOwnerStateDescription></rptOwnerStateDescription>
        </reportingOwnerAddress>
        <reportingOwnerRelationship>
            <isDirector>1</isDirector>
            <isOfficer>0</isOfficer>
            <isTenPercentOwner>0</isTenPercentOwner>
            <isOther>0</isOther>
        </reportingOwnerRelationship>
    </reportingOwner>

    <remarks>Exhibit List: Exhibit 24 - Power of Attorney</remarks>

    <ownerSignature>
        <signatureName>/s/ Kenneth R. Pina, attorney-in-fact</signatureName>
        <signatureDate>2017-11-17</signatureDate>
    </ownerSignature>
</ownershipDocument>
