Introduction: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been spreading all over the world, including India; the virus has been classified in various clades (L, S, V, G, GH, GR, and others) on the base of mutations. India is vulnerable to the health and financial hazards of the SARS-CoV-2 infection. Even after four phases of lockdown, the number of SARS-CoV-2 infections has been increasing in India. Clinical trials for vaccine and ribonucleic acid (RNA)-dependent RNA polymerase inhibitor are going on. The study was conducted to analyze SARS-CoV-2 genomic sequences submitted from India to identify mutations and their geographical distribution. Material and Methods: Three hundred and sixty-three sequences submitted from India were archived (GISAID database), compared with reference sequence (Wuhan, China), and phylogenetic tree was prepared. Sequences with more than 1% nucleotide stretching were excluded for mutation analysis, and multiple sequence analysis for 317 sequences was done. Mutations were analyzed as per phases of lockdown and geographical distribution. Results: Clade “GH” appears in the second and third phases of lockdown; the clade “V” has not been reported after March 17, 2020, in India. Spike protein mutation D614G was found in 166 sequences, out of which 164 sequences show P323 L mutation of nonstructural protein 12 (nsp12). RNA-dependent RNA polymerase coding nsp12 shows 23 types of 364 amino acid mutations. Discussion and Conclusion: SARS-CoV-2 shows increasing mutations with the time and spread of the virus. The mutations in spike protein and nsp12 regions are critical for response to undergoing trials of vaccines and drugs.