Introduction The differences of functional connectivity (FC) and functional asymmetry between left and right mesial temporal lobe epilepsy with hippocampal sclerosis (LMTLE and RMTLE) have not been completely clarified yet. The purpose of the present study is to investigate the FC changes and the FC asymmetric patterns of MTLE, and to compare the differences in FC and functional asymmetry between LMTLE and RMTLE. Methods In total, 12 LMTLE, 11 RMTLE patients, and 23 healthy controls (HC) were included. Region of interest (ROI)-based analysis was used to evaluate FC. The right functional connectivity (rFC) and left functional connectivity (lFC) of each ROI were calculated. Asymmetry index (AI) was calculated based on the following formula: AI=100x(rFC-lFC)/[(rFC+lFC)/2]${\rm{AI\ }} = {\rm{\ }}100{\rm{\ }} \times {\rm{\ }}( {{\rm{rFC}} - {\rm{lFC}}} )/[ {( {{\rm{rFC}} + {\rm{lFC}}} )/2} ]$. Paired t-test and univariate analysis of variance were used to analyze FC asymmetry. Linear correlation analysis was performed between significant FC changes and lateralized ROIs and epilepsy onset age and duration. Results LMTLE and RMTLE patients showed different patterns of alteration in FC and functional asymmetry when compared with controls. RMTLE presented more extensive FC abnormalities than LMTLE. Regions in ipsilateral temporal lobe presented as central regions of abnormalities in both patient groups. In addition, the asymmetric characteristics of FC were reduced in MTLE compared with HC, with even more pronounced reduction for RMTLE group. Meanwhile, ROIs presented FC AI differences among the three groups were mostly involving left temporal lobe (L_hippo, L_amyg, L_TP, L_aMTG, and L_pTFusC). No correlation was found between significant FC changes and lateralized ROIs and epilepsy onset age and duration. Conclusion The FC and asymmetric features of MTLE are altered and involve both the temporal lobe and extra-temporal lobe. Furthermore, the altered FC and asymmetric features were distinctly affected in LMTLE and RMTLE compared to controls.