Poly(diketopyrrolopyrrole) (PDPP)-based π-conjugated polyelectrolytes (CPEs), facilitating either electron or hole transport for applications in organic electrochemical transistors (OECTs), were synthesized. By equipping each polymer main-chain with neutral, anionic, or cationic side chains, the resulting series of polymers encompasses all possible combinations of negative, positive, and neutral side-chain ionic charges in combination with in situ-generated holes or electrons on the backbone. This investigation focuses on uncovering intramolecular synergies and antagonisms of the mixed conductors (ions and electrons), with a special emphasis on parameters relevant to both p- and n-type OECT devices using CPEs. While UV–vis absorption spectroscopy suggests only small changes in the optoelectronic properties among the differently charged polymers, in situ and operando GIWAXS analyses revealed significant differences in swelling behavior. We observed that cationic and anionic side chains induce distinct alterations in interlamellar spacing with varying degrees of swelling influenced by electrochemical doping and ion diffusion, which is controlled by the sign of the applied potential. Anionic side chains favor hole transport and enable an earlier oxidation onset of the donor CPE, as demonstrated in the OECT and spectroelectrochemistry (SEC) studies. Such changes are crucial for improving the p-type OECT efficiency and responsiveness. The opposite effect is observed in cationic polyelectrolyte hole conductors. Conversely, electron-transporting materials benefit from cationic side chains, while anionic side chains prove detrimental for n-type device operation. These results suggest a general design strategy for anionic or cationic donor and acceptor materials for the exploitation of OECT applications, where the formation and transport of charge carriers formed in operando (electrons or holes) are favored by the opposite side-chain ions immobilized in a CPE chain, resulting in high drain current at low gate voltages, improved transconductance, and low redox onset voltage.