The Last Interglacial (LIG; ~130,000 to 116,000 years ago) is the most recent period from the past with warmer-than-present climate. Thus, climate reconstructions from the LIG provide an excellent opportunity to evaluate current and projected future climatic trends against natural climate variability from the warmer world. However, long and continuous records of LIG climate at subdecadal resolution have been elusive due to a small number of suitable geological records and limitations of conventional methodologies for estimating past climate. We circumvented these issues by applying submillimeter-resolution Mass Spectrometry Imaging (MSI) of organic compounds on finely laminated sapropel sediment deposited during the LIG in the Eastern Mediterranean. We rely on an unusually thick S5 sapropel layer recovered in the sediment core M51/3-SL104 (34.8247°N, 27.2925°E; water depth 2155 m) from the Pliny Trench region of the Eastern Mediterranean collected during the RV METEOR M51-3 expedition cruise from La Valetta to Istanbul. MSI was performed using a 7T solarix XR Fourier transform-ion cyclotron resonance-mass spectrometer (FT-ICR-MS) coupled to a matrix-assisted laser desorption/ionization (MALDI) source equipped with a Smartbeam II laser. The resulting time-series of alkenone-based sea surface temperature (SST) covers ~4.800 years in 1-4 year resolution. In the dataset are presented depth, age, UK'37 values, as well as lower and higher estimates of UK'37 interhorizontal data variability, calibrated SST time-series and associated uncertainty, as well as intensities of isorenieratene. Moreover, we provide UK'37 values for 12 samples in 1-2 cm resolution and associated SST obtained by gas chromatography. We also provide the time slice climate simulations performed with version 1.2.2 of the Community Earth System Model (CESM1.2) SST model projection under RCP4.5 and RCP8.5 for the same location between 2021 and 2099 in order to compare natural LIG SST variability with the projected SST variability form future warmer-than-present world.