typedef enum {
    ENDIAN_NATIVE,
    ENDIAN_NETWORK,
    ENDIAN_LITTLE,

    ENDIAN_BIG = ENDIAN_NETWORK
} ENDIANNESS;


int
magic_get_uint16(pTHX_ SV *sv, MAGIC *mg)
{
    STRLEN len;
    SV* const src_sv = LvTARG(sv);
    const char* const src_mem = SvPV_const(src_sv, len);
    STRLEN ofs = LvTARGOFF(sv);
    ENDIANNESS endianness = (ENDIANNESS)LvTARGLEN(sv);
    U16 dst;

    /* We use a PVLV instead of storing an SV in the magic */
    PERL_UNUSED_ARG(mg);

    if (ofs >= len/2)
        croak("Index outside of mmap");

    ofs *= 2;

    if (endianness == ENDIAN_LITTLE)
        dst = (src_mem[ofs+1] << 8) | src_mem[ofs+0];
    else if (sizeof(U16) != 2 || endianness == ENDIAN_NETWORK)
        dst = (src_mem[ofs+0] << 8) | src_mem[ofs+1];
    else {
        *(((char*)&dst)+0) = src_mem[ofs+0];
        *(((char*)&dst)+1) = src_mem[ofs+1];
    }

    sv_setuv(sv, dst);

    return 0;
}


int
magic_set_uint16(pTHX_ SV *sv, MAGIC *mg)
{
    STRLEN len;
    SV* const dst_sv = LvTARG(sv);
    char* const dst_mem = SvPV(dst_sv, len);
    STRLEN ofs = LvTARGOFF(sv);
    ENDIANNESS endianness = (ENDIANNESS)LvTARGLEN(sv);
    UV num
    U16 src;

    /* We use a PVLV instead of storing an SV in the magic */
    PERL_UNUSED_ARG(mg);

    SvUV(sv);
    if (!SvIOK(sv))
        croak("Invalid value: Not a integer");

    num = SvUVX(sv);
    if (num > 65535)
        croak("Invalid value: Not a 16-bit integer");

    src = (U16)num;

    if (ofs >= len/2)
        croak("Index outside of mmap");

    ofs *= 2;

    if (endianness == ENDIAN_LITTLE) {
        dst_mem[ofs+0] = src & 0xFF;
        dst_mem[ofs+1] = src >> 8;
    }
    else if (sizeof(U16) != 2 || endianness == ENDIAN_NETWORK) {
        dst_mem[ofs+0] = src >> 8;
        dst_mem[ofs+1] = src & 0xFF;
    }
    else {
        dst_mem[ofs+0] = *(((const char*)&src)+0);
        dst_mem[ofs+1] = *(((const char*)&src)+1);
    }

    return 0;
}
[download]

It would simplify things to case src_mem/dst_mem to *U16, but U16 can be more than 16 bits and it introduces alignment issues.

I made the native byte ordering big endian on systems where there is no 16-bit unsigned int.