Studies on the paradigm of the preferred movement path are scarce, and as a result, many aspects of the paradigm remain elusive. It remains unknown, for instance, how muscle activity adapts when differences in joint kinematics, due to altered running conditions, are of low / high magnitudes. Therefore, the purpose of this work was to investigate changes in muscle activity of the lower extremities in runners with minimal (≤ 3°) or substantial (> 3°) mean absolute differences in the ankle and knee joint angle trajectories when subjected to different running footwear. Mean absolute differences in the integral of the muscle activity were quantified for the tibialis anterior (TA), peroneus longus (PL), gastrocnemius medialis (GM), soleus (SO), vastus lateralis (VL), and biceps femoris (BF) muscles during over ground running. In runners with minimal changes in 3D joint angle trajectories (≤ 3°), muscle activity was found to change drastically when comparing barefoot to shod running (TA: 35%; PL: 11%; GM: 17%; SO: 10%; VL: 27%; BF: 16%), and minimally when comparing shod to shod running (TA: 10%; PL: 9%; GM: 13%; SO: 8%; VL: 8%; BF: 12%). For runners who showed substantial changes in joint angle trajectories (> 3°), muscle activity changed drastically in barefoot to shod comparisons (TA: 39%; PL: 14%; GM: 16%; SO: 16%; VL: 25%; BF: 24%). It was concluded that a movement path can be maintained with small adaptations in muscle activation when running conditions are similar, while large adaptations in muscle activation are needed when running conditions are substantially different.