Thermosensitive polymers such as poly(N-isopropylacrylamide) (PNIPAM) undergo a phase transition in aqueous solution from a random-coil structural ensemble to a globule structural ensemble at the lower critical solution temperature (LCST). Above this temperature, PNIPAM agglomerates and becomes insoluble, whereas it is soluble below the temperature. Thus, thermosensitive polymers represent essential targets for several applications, e.g., in drug delivery. Although their ability to change structure in response to a temperature alteration is highly relevant for industrial processes, their thermodynamic properties are mostly qualitatively understood, and the quantitative thermodynamic picture is still elusive. In this study, we used a combined atomistic molecular dynamics and well-tempered metadynamics simulation approach to estimate coil-globule transition thermodynamics. An isotactic 30-mer of PNIPAM was investigated over a broad temperature range between 200 and 360 K. The transition from the globule to the random-coil structure was observed with well-tempered metadynamics. For the first time, the free energy surface of PNIPAM was estimated and it is shown that the simulation results are in line with the experimentally observed thermosensitive behavior. Below the LCST, the random-coil ensemble represents the global energy minimum and is thermodynamically favored by 21 ± 9 kJ/mol compared to the globule ensemble; both are separated by a barrier of 49 ± 14 kJ/mol. In contrast, above the LCST, the globule ensemble is thermodynamically favored by 21 ± 8 kJ/mol over the random-coil ensemble. The barrier from random-coil to globule is 17 ± 10 kJ/mol.