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We are remarkably adept at inferring the consequences of our actions, yet the neuronal mechanisms that allow us to plan a sequence of novel choices remain unclear. We used functional magnetic resonance imaging (fMRI) to investigate how the human brain plans the shortest path to a goal in novel mazes with one (shallow maze) or two (deep maze) choice points. We observed two distinct anterior prefrontal responses to demanding choices at the second choice point: one in rostrodorsal medial prefrontal cortex (rd-mPFC)/superior frontal gyrus (SFG) that was also sensitive to (deactivated by) demanding initial choices and another in lateral frontopolar cortex (lFPC), which was only engaged by demanding choices at the second choice point. Furthermore, we identified hippocampal responses during planning that correlated with subsequent choice accuracy and response time, particularly in mazes affording sequential choices. Psychophysiological interaction (PPI) analyses showed that coupling between the hippocampus and rd-mPFC increases during sequential (deep versus shallow) planning and is higher before correct versus incorrect choices. In short, using a naturalistic spatial planning paradigm, we reveal how the human brain represents sequential choices during planning without extensive training. Our data highlight a network centred on the cortical midline and hippocampus that allows us to make prospective choices while maintaining initial choices during planning in novel environments., Using neuroimaging and computational modelling, this study explains how the human brain represents initial versus subsequent choices during spatial planning in novel environments., Author Summary We are remarkably adept at inferring the consequences of our actions, even in novel situations. However, the neuronal mechanisms that allow us to plan a sequence of novel choices remain a mystery. One hypothesis is that anterior prefrontal brain regions can jump ahead from an initial decision to evaluate subsequent choices. Here, we examine how the brain represents initial versus subsequent choices of varying difficulty during spatial planning in novel environments. Specifically, participants visually searched for the shortest path to a goal in pictures of novel mazes that contained one or two path junctions. We monitored the participants’ brain activity during the task with functional magnetic resonance imaging (fMRI). We observed, in the anterior prefrontal brain, two distinct responses to demanding choices at the second junction: one in the rostrodorsal medial prefrontal cortex (rd-mPFC), which also signalled less demanding initial choices, and another one in the lateral frontopolar cortex (lFPC), which was only engaged by demanding choices at the second junction. Notably, interactions of the rd-mPFC with the hippocampus, a region associated with memory, increased when planning required extensive deliberation and particularly when planning led to accurate choices. Our findings show how humans can rapidly formulate a plan in novel environments. More broadly, these data uncover potential neural mechanisms underlying how we make inferences about states beyond a current subjective state.