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BP214 is an all-D antimicrobial peptide amide, kklfkkilryl, which shows an excellent activity against colistin-resistant <i>Acinetobacter baumannii</i> and a low hemolytic activity. The aim of the present work was to investigate how <i>C</i>-terminus-to-side chain macrocyclization and fatty acid modification affect the antimicrobial and hemolytic activity of this peptide. In total, 18 analogs of BP214 were synthesized using a combination of Fmoc-based solid-phase peptide synthesis and the submonomer approach. Cyclization was achieved by reacting the ε-amino group of a <i>C</i>-terminal lysine residue with a bromoacetylgroup attached to the <i>N^α</i> amino group of the N-terminal amino acid, generating a secondary amine at which the exocyclic lipopeptide tail was assembled. Three different ring sizes (i.e., 3–5 amino acid residues) of <i>C</i>-locked analogs combined with fatty acids of different lengths (i.e., C₁₀–C₁₄) were investigated. The antimicrobial activity of the analogs was tested against <i>Staphylococcus aureus</i>, <i>Escherichia coli, Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, and <i>Pseudomonas aeruginosa</i>. The most promising compound was analog <b>13</b> (MIC = 4 µg/mL (2.4 µM) against <i>E. coli</i> and 36% hemolysis of red blood cells at 150 µM). In a time-kill assay, this peptide showed a significant, concentration-dependent reduction in viable <i>E. coli</i> cells comparable to that seen for colistin.