Learning new rules rapidly and effectively via instructions is ubiquitous in our daily lives, yet the underlying cognitive and neural mechanisms are complex. Using functional magnetic resonance imaging we examined the effects of different instructional load conditions (4 vs. 10 stimulus-response rules) on functional couplings during rule implementation (always 4 rules). Focusing on connections of lateral prefrontal cortex (LPFC) regions, the results emphasized an opposing trend of load-related changes in LPFC-seeded couplings. On the one hand, during the low-load condition LPFC regions were more strongly coupled with cortical areas mostly assigned to networks such as the fronto-parietal network and the dorsal attention network. On the other hand, during the high-load condition, the same LPFC areas were more strongly coupled with default mode network areas. These results suggest differences in automated processing evoked by features of the instruction and an enduring response conflict mediated by lingering episodic long-term memory traces when instructional load exceeds working memory capacity limits. The ventrolateral prefrontal cortex (VLPFC) exhibited hemispherical differences regarding whole-brain coupling and practice-related dynamics. Left VLPFC connections showed a persistent load-related effect independent of practice and were associated with ‘objective’ learning success in overt behavioral performance, consistent with a role in mediating the enduring influence of the initially instructed task rules. Right VLPFC's connections, in turn, were more susceptible to practice-related effects, suggesting a more flexible role possibly related to ongoing rule updating processes throughout rule implementation.